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MedChemica Publication by Year
Most highly cited indicated with ‡.


Cyanocyclopropylcarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases

37. Cyanocyclopropylcarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases. Dossetter, Alexander Graham; Heron, Nicola Murdoch PCT Int. Appl. (2008), WO 2009001129.


1,2-Cyclohexanedicarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases

36. 1,2-Cyclohexanedicarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases. Dossetter, Alexander Graham; Heron, Nicola Murdoch. PCT Int. Appl. (2008), WO 2009001128.


Cyanocyclopropylcarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases

35. Cyanocyclopropylcarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases. Crawford, James John; Dossetter, Alexander Graham; Finlayson, Jonathan Erle; Heron, Nicola Murdoch. PCT Int. Appl. (2008), WO 2009001127.


Preparation of amide-indoles as antagonists of gonadotropin releasing hormone (GnRH)

34. Preparation of amide-indoles as antagonists of gonadotropin releasing hormone (GnRH).      Wardleworth, James Michael; Dossetter, Alexander Graham; Halsall, Christopher Thomas.  (Astrazeneca AB, Swed.; Astrazeneca UK Limited).    PCT Int. Appl. (2002), 61 pp.  WO 2002092565  


Preparation of 6H-thieno[2,3-b]pyrrole derivatives as antagonists of gonadotropin-releasing hormone (GnRh) for treating sex hormone related conditions

33. Preparation of 6H-thieno[2,3-b]pyrrole derivatives as antagonists of gonadotropin-releasing hormone (GnRh) for treating sex hormone related conditions.      Foote, Kevin Michael; Matusiak, Zbigniew; Dossetter, Alexander Graham; Arnould, Jean Claude; Lamorlette, Maryannick Andree; Delouvrie, Benedicte; Hamon, Annie.  (AstraZeneca AB, Swed.; AstraZeneca UK Limited).    PCT Int. Appl.  (2004),     215 pp.   WO2004018480  A1 


Amine derivatives of imidazo[1,2-a]pyridine useful as antagonists of gonadotropin releasing hormone

32. Amine derivatives of imidazo[1,2-a]pyridine useful as antagonists of gonadotropin releasing hormone.      Dossetter, Alexander Graham; Kenny, Peter; McKerrecher, Darren; Wardleworth, Michael.  (Astrazeneca AB, Swed.; Astrazeneca UK Limited).    PCT Int. Appl. (2002), WO2002066478


Preparation of substituted imidazopyridines for antagonizing gonadotropin releasing hormone activity

31. Preparation of substituted imidazopyridines for antagonizing gonadotropin releasing hormone activity.      Dossetter, Alexander Graham; Kenny, Peter; McKerrecher, Darren; Wardleworth, Michael.  (Astrazeneca AB, Swed.; Astrazeneca UK Limited).    PCT Int. Appl. (2002), 98 pp. WO2002066477A2  


Preparation of cyanoguanidinoethylindoles GnRH antagonists

30. Preparation of cyanoguanidinoethylindoles GnRH antagonists.      Wardleworth, Michael; Dossetter, Alexander Graham; Halsall, Chris T.  (Astrazeneca AB, Swed.; Astrazeneca UK Limited).    PCT Int.Appl. (2002), 65 pp. WO2002066459  


Catalytic asymmetric cycloaddition reactions of dienes and aldehydes

29. Catalytic asymmetric cycloaddition reactions of dienes and aldehydes.      Jacobsen, Eric N.; Schaus, Scott E.; Dossetter, Alexander G.; Jamison, Timothy F.  (Harvard University, USA).    U.S.  (2001), 39 pp., US 6,130,340. 

28. Asymmetric cycloaddition reactions using transition metal chiral Schiff base complexes.      Jacobsen, Eric N.; Schaus, Scott E.; Dossetter, Alexander G.; Jamison, Timothy F.  WO 2000050365A1  


4-Amino-7,8-Dihydropyrimido[5,4-F][1,4]Oxazepin-5(6h)-One Based Dgat1 Inhibitors

27. 4-Amino-7,8-Dihydropyrimido[5,4-F][1,4]Oxazepin-5(6h)-One Based Dgat1 Inhibitors Birch, A. M.; Goldberg, F. W.; Leach, A. WO 2011121350.


Adamantyl Iminocarbonyl-Substituted Pyrimidines As Inhibitors Of 11-Beta-HSD1

26. Adamantyl Iminocarbonyl-Substituted Pyrimidines As Inhibitors Of 11-Beta-HSD1  Bennett, S. N. L.; Goldberg, F. W.; Leach, A.; Whittamore, P. R. O.; Sörme, P. US20110092526.


Pyrazine Carboxamides As Inhibitors Of DGAT1

25. Pyrazine Carboxamides As Inhibitors Of DGAT1 Birch, A. M.; Butlin, R. J.; Campbell, L.; Green, C.; Leach, A.; Murray, P. M.; Ryberg, P. O.; Waring, M. J. WO/2010/146395.


Substituted Pyrimidin-5-Carboxamides

24. Substituted Pyrimidin-5-Carboxamides Gill, A. L.; Leach, A.; Packer, M.; Scott, J. S.; Sörme, P.; Swales, J. G.; Whittamore, P. R. O. WO/2009/130496.


Carbamoyl compounds as DGAT1 inhibitors

23. Carbamoyl compounds as DGAT1 inhibitors. Bauer, U. A.; Birch, A. M.; Butlin, R. B.; Green, C.; Barlind, J. G.; Hovland, R.; Johannesson, P.; Leach, A.; Noeske, A. T.; Petersson, A. U. WO/2009/081195


Pyrrolo [2, 3 -d] pyrimidin derivatives as protein kinase B inhibitors

22. Pyrrolo [2, 3 -d] pyrimidin derivatives as protein kinase B inhibitors. Johnson, P. D.; Leach, A; Luke, R. W. A.; Matusiak,  Z. S.; Morris, J. J. WO/2009/047/563.


Substituted piperidines having protein kinase inhibiting activity

21. Substituted piperidines having protein kinase inhibiting activity Woodhead, S. J.; Frederickson, M.; Hamlett, C.; Woodhead, A. J.; Verdonk, M. L.; Sore, H. F.; Walker, D. W.; Blurton, P.; Collins, I.; Cheung, K. M.; Caldwell, J.; Da Fonseca Mchardy, T. F.; Luke, R. W. A.; Matusiak, Z. S.; Leach, A.; Morris, J. J. WO/2008/075109.


Piperidine derivatives for the treatment of obesity

20. Piperidine derivatives for the treatment of obesity Butlin, R. J.; Caulkett, P. W. R.; Leach, A.; Newcombe, N. J.; O’Donnell, C. J.; Wood, J. M. WO/2008/075077.


Piperidine derivatives for the treatment of obesity

19. Piperidine derivatives for the treatment of obesity Butlin, R. J.; Caulkett, P. W. R.; Leach, A.; Newcombe, N. J.; O’Donnell, C. J.; Wood, J. M. WO/2008/075064.


Sulfonamide derivatives for therapeutic use as fatty acid synthase inhibitors

18. Sulfonamide derivatives for therapeutic use as fatty acid synthase inhibitors Butlin, R. J.; Caulkett, P. W. R.; Johanesson, P.; Knerr, L. D.; Leach, A.; Newcombe, N. J.; O’Donnell, C. J.; Pointon, H.; Wood, J. M. WO/2008/075070.


Pyrimidine derivatives as EphB4 inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer

17. Pyrimidine derivatives as EphB4 inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. Kettle, J. G.; Read, J.; Leach, A.; Barlaam, B. C.; Ducray, R.; Lambert-Van der Brampt, C. M. P. WO/2007/085833.


Preparation of acylamino dibenzothiophenes as DNA-PK inhibitors

16. Preparation of acylamino dibenzothiophenes as DNA-PK inhibitors
Frigerio, Mark; Hummersone, Marc Geoffrey; Menear, Keith Allan; Finlay, Maurice Raymond Verschoyle; Griffen, Edward Jolyon; Ruston, Linette Lys; Morris, Jeffrey James; Ting, Attila Kuan Tsuei; Golding, Bernard Thomas; Griffin, Roger John; et al WO 2010136778 A1.


Preparation of 2-benzimidazolyl-6-morpholino-4-(piperidin-4-yl)pyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease

15. Preparation of 2-benzimidazolyl-6-morpholino-4-(piperidin-4-yl)pyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease
Butterworth, Sam; Griffen, Edward Jolyon; Pass, Martin WO 2008032072 A1.


Preparation of 2-benzimidazolyl-6-morpholino-4-heterocyclylpyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease

14. Preparation of 2-benzimidazolyl-6-morpholino-4-heterocyclylpyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease
Butterworth, Sam; Griffen, Edward Jolyon; Pass, Martin WO 2008032028 A1.


Preparation of 2-benzimidazolyl-6-morpholino-4-phenylpyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease

13. Preparation of 2-benzimidazolyl-6-morpholino-4-phenylpyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease Butterworth, Sam; Griffen, Edward Jolyon; Pass, Martin WO 2008032086 A1.


Preparation of 4-benzimidazolyl-2-morpholino-6-piperazinyl-pyrimidine derivatives as PI3K and mTOR kinase inhibitors for the treatment of proliferative disorder

12. Preparation of 4-benzimidazolyl-2-morpholino-6-piperazinyl-pyrimidine derivatives as PI3K and mTOR kinase inhibitors for the treatment of proliferative disorder Butterworth, Sam; Griffen, Edward Jolyon; Hill, George Beresford; Pass, Martin WO 2008032033 A1.


Conference Talks

“A Field Manual for Medicinal Chemistry: Towards Real AI in Drug Hunting?” Leventhal Lecture at CUP XX

Keynote lecture at Openeye Scientific’s CUP XX meeting

Presented by Dr Ed Griffen March 11th 2020.

Available with notes on slideshare.


Accelerating lead optimisation with active learning by exploiting MMPA based ADMET knowledge with regression forest potency models

Poster presented by Dr Ed Griffen at the 15th German Conference on Cheminformatics in Mainz, November 2019.

Available on slideshare.


Understanding Patent SAR by network analysis

Applying graph methodology to the relationships between patent compounds described by matched molecular pair analysis we can extract critical compounds within patents, the relationships between patents and even model potency.

Poster presented at the RSC 2018 kinase meeting on slideshare


Virtual Toxicity Panels to Aid the medicinal chemist

Poster presented on interpretable machine learning methods to model critical toxicities and provide clear guidance to the medicinal chemist.

Poster on slideshare


The MedChemica Bucket List

BucketListPapers 79/100: Designing CNS penetrant drugs….maybe the hardest thing?

blood brain schema

Perhaps the hardest medicinal chemistry challenge is taking a series of compounds, and modifying them, so they pass through the blood brain barrier. Such drug discovery projects have enlarged testing cascades, and usually require an early in-vitro absorption assay, and secondary rodent pharmacokinetics experiments to measure concentration of drug in the brain compartment. As such the cycle times around the Design-Make-Test-Analyse are protracted. The need for clear understanding of the processes involved, and the properties required in molecules, to reduce the number of cycles is paramount. We selected the review “Demystifying brain penetration…” as this gives a broad summary of the understanding so far.

Demystifying brain penetration in central nervous system drug discovery.

J. Med. Chem. 2013, 56, 2−12. 

In recent years the “CNS MPO” score, which can be calculated at the point of design, has gained popularity, so it is worth referencing this paper too.

Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties

ACS Chem. Neurosci. 2010, 1, 435–449


However, the CNS MPO score might become dated, as further understanding of the transporters involve rises. It might be that the count of number of Hydrogen Bond Donor (HBD) might be the key predictor.

How hydrogen bonds impact P-glycoprotein transport and permeability.

Bioorg. Med. Chem. Lett. 2012, 22, 6540−6548.

And lastly a couple of medchem papers on series that were optimised for CNS penetration:

The design and identification of brain penetrant inhibitors of phosphoinositide 3- kinase α.

J. Med. Chem. 2012, 55, 8007−8020.

Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice

J. Med. Chem. 2014, 57, 970−986

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 78/100: Improving on existing drugs, covalent binders and the late LO medicinal chemistry

Tagrisso discovery Fig2

A successful drug in the clinic is the final proof that modulation of a protein target yields benefits. The drug in question may have limitations, such as side-effects from off-target toxicity, dose limited efficacy and the such like. As such drug discovery program ‘restart’ with the aim of making a ‘gold-standard’ treatment, armed with a wealth of data and understanding from the clinic. These programs can be difficult and have protracted testing cascades as a large quantity of measurements are required to demonstrate superiority.

This paper is one of host of recent examples with the aim optimising for a specific mutation of the protein target and off-target effects. The selectivity is gained using the covalent binding group and off-target selectivity (IGFR) is achieved by a combination of groups, shown by some excellent matched pair analysis. This in itself is great medicinal chemistry, but the paper also describes some of the trials and tribulations of late LO and early pre-clinical, including a small amount of human PK data.

Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor

J. Med. Chem. 2014, 57, 20, 8249–8267

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 77/100: The first tyrosine kinase inhibitor…

gleevec discovery

Perhaps this paper is showing its age, but at the time BMCL papers were basic, with just a table of two of measurements and simple synthesis. Non the less, this is the paper describing the discovery of a candidate drug (1) that went on to become the product Gleevec (Imatinib); this first tyrosine kinase inhibitor (the Wikipedia page has more data). The drug made quite an impact on many patients lives. Looking back, with experienced eyes, we can see the structural features now present in ATP binding pocket kinase inhibitors. The research process was rational and screened multiple kinases, leading by careful SAR analysis to 1. Tne compound, which is quite selective, in part due to the methyl group on the central ring. Of note is the ‘pan’ kinase inhibitor 9 – this compound might be worth adding to your compound collections, such that early screening could yield a tool compound?

Imatinib – Potent and selective inhibitors of the Abl-kinase: phenylamino-pyrimidine (PAP) derivatives

Bioorg. & Med. Chem. Lett. 1997, 7, 187-192 

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 76/100: Macrocyclisation as the route to success?

Loriatinib macrocyclisation

The story of Lorlatinib started with an existing inihibitor and used macrocyclization to improve properties. Macrocyclisation has been a recent approach to improving small molecules, and is usually performed as part of a structure-based design program. The ideal starting point is a high quality x-ray structure determination of the small molecule bound to protein, thats shows the molecule is folded, in such a way, that groups in the molecules are close enough together to ‘join up’, thus forming a large ring. The difference in entropy on the binding can be significant and can yield highly potent compounds. In addition, these macrocycles present different shapes and have been demonstrated to have improved absorption and reduced efflux. Although the approved drug Crizotinib has robust efficacy in ALK-positive tumors, patients eventually develop resistance, and metastases to the brain can occur. Many cancer drugs have poor penetration across the Blood Brain Barrier (BBB), so a new suite of kinase inhibitors with high brain blood concentration is highly desirable. The authors in this paper started from Crizothinib and initially made acyclic compounds, focussing on efficient small molecules (low LipE) to improve brain penetration (see references within).  Co-crystallisation of these inhibitors in ALK showed the compounds were folded in the U-shape, positioning two aryl groups close together (see Figure 3). The idea for macrocyclic compounds was born, but this was not without difficulties. The paper describes in great detail the medicinal chemistry and synthetic chemistry challenges and is rich in data and analysis.


Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.

J. Med. Chem. 2014, 57, 11, 4720–4744

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 75/100: Starting from the natural substrate as a drug hunting lead : a modern example.

brillinta SAR

Before the days of high through screening, starting from the natural substrate was the method of generating chemical leads for drug discovery. Beginning with ATP, a quite poor lead for an oral programme, a potent P2Y12 antagonists with found. Remarkably all the elements in the medicinal chemical journey have been crammed into this BMCL paper! Of note is the replacement of the labile triphosphate group and increasing affinity with a triazolopyrimidine core and introducing a trans-2-phenylcyclopropylamino substituent. The resultant drug Ticagrelor is quite complex and the manufacturing route is whole other story too.


From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis.

Bioorg. & Med. Chem. Lett. 2007, 17, 6013-6018

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 74/100: Unusual chemical groups can make it into drugs.

Vaborbactam design idea

Carbapenem-resistant Enterobacteriaceae (CRE), due to the Klebsiella pneumoniae carbapenemase (KPC) and other β-lactamases, now threatens the usefulness of all β-lactam antibiotics. Boronic acids offered an intriguing group to mimic the transition state of the lactamases and were already known. The research took a highly modern approach of modelling possibilities and generated a new series with a novel cyclic boronic acid. In this manner very few compounds were actually made and profiled – a great example of a highly rationale approach and modern molecular modelling.

Vaborbactam – Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases.

J. Med. Chem. 2015, 58, 9, 3682–3692

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 73/100: Amide isosteres and fluorines in the right place.

sitagliptin xtal

The discovery of Sitagliptin is a story of finding an amide isostere that worked, then optimisation of pharmacokinetics via some fluorines in the right place. Metabolically labile amides can be replaced 5 membered heterocycles, where a lone pair of an aromatic N mimics the H-bonding of an amide carbonyl. Here the scientists at Pfizer combined this by “fusing” the five membered ring into a piperazine to generate a novel heterocycle. The rest of the optimisation was finding a CF3 group was optimal for bio-availability, although the reason for this is not clear. Interestingly, a pattern of fluorine atoms on the end benzene ring enhanced binding, and subsequent x-ray structure determination of the molecule bound to protein showed how good the fit was.

SITAGLIPTIN[MK-0431] (2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:  A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

J. Med. Chem. 2005, 48, 1, 141–151

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 72/100: Improving pharmacokinetics and reactive metabolites.

Suvorexant discovery

Lead optimisation frequently includes involves work to improve bio-availability, lower clearance and improve solubility. In addition, early safety studies take place, and usually this is the first time more details emerge of the fate of leading compounds in-vivo. The formation of reactive metabolites is undesirable as they could cause drug-induced idiosyncratic toxicity in humans. The work by Merck for a new insomnia drug involved optimisation of PK and elimination reactive metabolites; the solution was a completely different aromatic group, one that overall, yielded a compound that was more lipophilic than the advanced yield.

Suvorexant – Discovery of the Dual Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia.

J. Med. Chem. 2010, 53, 14, 5320–5332.

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 71/100: Thinking through the chemistry paves the way to success.

Daclatasvir discovery

A triumph of the decade (2010 – 2019) is the suite of Hepatitis C small molecule drugs treatments. These took a previously fatal disease to a 97% cure rate in 6 to 12 weeks of treatment. The second half of the decade saw the medicinal chemists involved presenting their work at major conferences. One of the most impressive of these talks, and it is reflected in the publication, was the discovery of Daclatasvir. By phenotypic screening a relatively unattractive hit was found and the SAR explored. The breakthrough came when the instability of the compound was examined and a dimerization process discovered. An almost complete rework occurred and the diligence of the chemists yielded a candidate drug with exquisite potency and high bio-availability. A remarkable piece of work.

Discovery of Daclatasvir, a Pan-Genotypic Hepatitis C Virus NS5A Replication Complex Inhibitor with Potent Clinical Effect

J. Med. Chem. 2014, 57, 12, 5057–5071

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 70/100: Overcoming a hERG inhibition problem.

CCR5 hERG problem

The GPCR receptors CCR5 and CCR4 are recognised on the surface of host T-cells by HIV virus particles. It was found that a group of the population had a mutation so their CCR5 receptors were not recognised and so did not get infected. This attractive target was tackled by many organisations and nearly all of them found similar chemical matter in the form of a bi-aryl group linked to a basic nitrogen. As these programs continued they coincided with the requirement for NCE to avoid (or be free of) any binding to the human ether a-go-go related gene product (aka hERG) ion-channel. The Pfizer research program had to optimise against this binding as well as bio-availability and in-vitro and in-vivo reduction of viral load.

Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc.

Bioorg. & Med. Chem. Lett. 2006, 16, 4633-4637.


Further hERG references:

Medicinal Chemistry of hERG Optimizations:  Highlights and Hang-Ups

J. Med. Chem. 2006, 49, 17, 5029–5046

hERG Me Out

J. Chem. Inf. Model. 2013, 53, 9, 2240–2251

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 69/100: Raltegravir: Optimising cellular activity due to blood protein binding.

Raltalgvir LO

HIV-Integrase was also discovered as another method of disrupting viral replication in host cells. Merck were working on multiple viral targets and had quality lead compounds, including inhibitors for Hepatitus-C. Combining leads into one series initial appeared unfruitful and the reason for doing this appears unclear. It is usual in anti-infective programs to measure IC95 inhibition, and also at assays containing blood serum, which can suppress the activity as free concentration of active compound is reduced. Without high virus suppression replication continues and the drug has next to no effect. This program is an illustration of a chemical series that was highly bound to blood proteins: an acidic core scaffold and a lipophilic aryl group, being the driver for this. The authors took the approach of looking at another part of the molecule, where polar groups can be added to modulate the blood protein binding. SAR exploration yielded two groups that resulted in candidate drugs.

Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection.

J. Med. Chem. 2008, 51, 18, 5843–5855

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 68/100: Indinavir – optimising by structure based design

Indinavir SAR table

It is perhaps not surprising that we have chosen three anti-HIV drug discovery projects. The failure to find a vaccine for HIV, in the second half of the eighties, launched a concerted push to develop small molecule drugs. This was building on the success of the nucleoside reverse transcriptase inhibitors (NRTI) compounds such as AZT. This effort coincided with improved Structure Based Drug Design (SBDD) via co-crystals and 3D modelling, and higher through-put in-vitro assays. The protease of HIV had been discovered and early compounds were shown to reduce virus load in-vitro. Using the transition state isostere concept hydroxyethylene dipeptide isostere inhibitors were designed and known. The story of the discovery of Indinavir starts with their own in-house inhibitors, and an early compound from Roche. These compounds had poor aqueous solubility and no bio-availability, but with 3D modelling the researches saw the opportunity of taking the basic nitrogen groups from the Roche compound into their series and this led to Indinavir.

Indinavir; L-735,524: The Design of a Potent and Orally Bioavailable HIV Protease Inhibitor.

J. Med. Chem. 1994, 37, 21, 3443–3451

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 67/100: From HTS hit to candiate drug.

Invacaftor discovery

Cystic fibrosis (CF) is a lethal genetic disease that affects approximately 70000 patients worldwide. The story of the discovery of Ivacaftor starts with a specialised high content screening campaign, which yielded a fairly average ‘looking’ hit. This modern discovery effort fully describes the complete work up and optimisation of a hit into a candidate drug – this is quite unusual, as many programs end up breaking down the work into several publications. On note is the full and detailed characterisation of the hit compound (about 2 uM), which put the project in a strong position. At this point a hit with a relatively low molecular weight of 368 and cLogP of 2.9, and well understood functional activity, was very attractive. The initial SAR exploration is excellent: a handful of well thought out compounds showed the binding mode of the series, and which tautomer form was key to binding – take note. The second exploration found a new hydrogen bond to explore and optimise, in the form of an indole. Take note again the team fully characterised this compound, and found excellent selectivity against a panel of protein targets, but poor solubility and sub-optimal pharmacokinetics – this again placed the project in a strong position. Next to understand the poor solubility the team proposed and modelled potential intramolecular hydrogen bonds and a planar structure, which were confirmed by a single crystal x-ray determinations – this is the definitive method. Efforts to disrupt the intramolecular H-bonds and planarity did find tert-butyl groups could be added. This approach would normally yield a molecule high in lipophilicity an unlikely to have good solubility. However, work to find an iso-steres to indole found a phenol group could be used. Normally a classic med-chem change is phenol to indole, but this is the reverse. Phenols are not normally desirable as they undergo secondary metabolism resulting in short half-life, but flanked with a t-butyl group this clearly does not occur as PK was good for this combination of groups.

Ivacaftor – Discovery of N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a Potent and Orally Bioavailable CFTR Potentiators.

J. Med. Chem. 2014, 57, 23, 9776–9795.

#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe


BucketListPapers 66/100: The first case study – Celecoxib – introducing a metabolically labile group to control half-life.

Selecting drug discovery case studies for the BucketList

Here starts a set of drug discovery ‘case studies’; selected papers that describes the research that led to an approved drug to market. If we just selected these papers on the basis of being an approved drug, we could probably generate another bucket list. We could also have chosen papers that are excellent examples of the current standard of scientific write ups. However, the most useful papers are those where the research has solved a particular problem, and this is well described, with clear tables of data. We think these papers have the most educational benefit, and serve as a good references. However there is a bias towards some of the more recent ‘drugs to market’, simple because of the standard of the write up, particular those in J.Med.Chem. Lastly, if we came across a paper that has been made open access by the authors, we selected that over others.

We should note some classics from history, as honourable mentions.

Let us mention the first beta-blocker: Propranolol which led to a Nobel prize. Black JW, Crowther AF, Shanks RG, Smith LH, Dornhorst AC (May 1964). “A New Adrenergic”.

Lancet. 1 (7342): 1080–1.

And Cimetidine, considered by many as the ‘first rationally designed’ drug.

Characterization And Development Of Cimetidine As A Histamine Hz-Receptor Antagonist. Gastroenterology 74:339-347, 1978

And the Captoprl story. Science, 1977, 196, 441-444.

On the subject of writing a quality med chem paper – please read:

Writing Your Next Medicinal Chemistry Article: Journal Bibliometrics and Guiding Principles for Industrial Authors

J. Med. Chem. 2020, 63, 14336−14356


Case Study : Celecoxib

Celecoxib SAR table

The inhibition of Cyclooxygenase-2 requires a molecule with a five membered ring substituted with a 1,2-diphenyl groups. The series discovered Pfizer was unusually stable, having an un-expectably long half-life in rodent. The solution was to introduce a metabolically labile group (4-Methyl – compound 1i – Table 1). This generally is the reverse of what is required in typical drug hunting projects, with the exception of inhaled drugs a short half-life is often desired. The approach to solving the problems, and late stage in-vivo profiling is well described.

Synthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors:  Identification of 4-[5-(4-Methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)

J.Med. Chem. 1997, 40, 9, 1347–1365

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BucketListPapers 65/100: Another invaluable list for your med chem knapsack.

Bad proteins in preclinical

We send this reference out to our clients and contacts more than any other paper. It describes the rationale, strategies and methodologies for in vitro pharmacological profiling at four major pharmaceutical companies (AstraZeneca, GlaxoSmithKline, Novartis and Pfizer), and illustrates, with examples of their impact, on the drug discovery process. For the first time there was a disclosed a list of proteins, that small molecule interaction has been linked to undesired side effects in patients. Such effects led to discontinuation of the drug at obvious high cost. The knowledge of this list, coupled with early in-vitro screening, is a must have for medicinal chemistry.

Reducing safety-related drug attrition: the use of in vitro pharmacological profiling.

Nature reviews Drug Discovery, 2012, 11, 909


BucketListPapers 64/100: Lipophilic candidate drugs tend to be discontinued.

Lipophilic and fate in dev

The first of these two papers, examining the physical chemical properties of drugs and the in-vivo and clinical outcomes, caused a stir when first published. This resulted in the one of the authors going ‘on tour’, around the conference circuit, for about a year, as we recall. A simple study comparing the properties of successful phase 1,2 and 3 drugs, against those that were discontinued produced a simple conclusion. Other properties were also examined and the authors subsequently produced more detailed studies that were subsequently only disclosed at conferences. The work led, we believe to the term ‘developability’, and various methods of calculating a score.

The second paper performs a more rigorous statistical study of compound properties and in-vivo outcomes. This work is quite detailed, and quite hard to follow the stats, but importantly the work considers the inter-connectivity of properties.

A Comparison of Physiochemical Property Profiles of Development and Marketed Oral Drugs

J. Med. Chem. 2003, 46, 7, 1250–1256

Relating Molecular Properties and in Vitro Assay Results to in Vivo Drug Disposition and Toxicity Outcomes

J.Med. Chem. 2012, 55, 14, 6455–6466.


BucketListPapers 63/100: Relating chemical properties to outcomes in early pre-clinical toxicology studies… and a missing conclusion?

Properties to tox

In early drug development, candidate compounds undergo testing in in-vivo animal safety models. The results of these are usually written up in text documents, and not usually broken up into data points to be loaded onto a database, for example. The drug discovery chemists of this bucket list paper took these “raw” text documents and entered the results into spreadsheets to allow study against the chemical properties of the drug candidates – this itself is pretty heroic. A complication of any analysis involving in-vivo data is the dose / concentration of compound in blood will be different from study to study. For statistical rigour, the group chose the 10uM Total Drug Threshold as there was an even number of “clean” versus “toxic” outcomes for the compounds studied. From this there came a ‘medicinal chemistry rule’: low-ClogP(<3)/high-TPSA(>75) are approximately 2.5 times more likely to be clean as to be toxic. However, the authors came to realise they had missed something in the analysis, and subsequently referred to it during conference talks. At the 1uM threshold (Figure 3 above) the majority of the compounds were clean. So highly potent compounds, with good bio-availability, enables low dosing is the best route to non-toxic results pre-clinically, irrespective of properties.

Physiochemical drug properties associated with in vivo toxicological outcomes

Bioorg. Med. Chem. Lett. 2008, 18, 4872 – 48755.

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BucketListPapers 61/100: How molecular shape modelling can aid drug discovery.

Molecular shape influence

This perspective provides a detailed description of the ways in which molecular shape is modelled and utilised to enhance drug discovery. The authors address how molecular shape modelling has impacted three questions essential in medicinal chemistry: “What is the essence of a molecule? What is it made of? What will it do?” Starting with virtual screening, the perspective details how programs like ROCS (rapid overlay of chemical structures) and SQW (SemiQuantitative reWrite) can be used to find new ligands for targets given a known ligand. These programs use atom-centred Guassians, coloured by atom type, to represent molecules as functionalised volumes that can be overlayed and compared. The authors also highlight the importance of molecular shape in lead optimisation; specifically for the identification of bioisosteres for the improvement of pharmacokinetic properties while maintaining or improving target potency. Furthermore, an extensive review of the use of molecular shape modelling in protein crystallography and ligand pose prediction is given, highlighting technologies and examples where both the molecular shape and torsional strain are optimised to provide realistic ligand poses. Molecular shape is also shown to be a useful metric in the design of diverse compound libraries with algorithms developed to design the molecular shape space of interest and cluster compounds into diverse shape clusters. The authors also describe examples of how Guassian-based molecular shape representations can aid in the design of protein-protein inhibitors, which are notoriously hard to design due to the flat nature of the protein interaction surfaces. Next, an alternative method for molecular shape description is introduced that describes the shape as a surface by placing the molecule in a grid of points in space and recording the minimal distances of the points to the molecular surface; a method that has been utilised for 3D QSAR modelling. Finally, the authors present a comparison of several approximate shape methods that provide quick results for pre-filtering large datasets before more exhaustive calculations can be performed.

In summary, understanding molecular shape can make an impact in many areas of drug discovery and a variety of Guassian or surface -based modelling programs have been developed to aid the medicinal chemist. This review offers an extensive description of such approaches and their example uses, and is a great read for those wishing to develop their understanding of the field.

Molecular Shape and Medicinal Chemistry: A Perspective Med. Chem. 2010, 53, 10, 3862–3886

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BucketListPapers 60/100: The General Solubility Equation.

general solubility equation

Compound solubility is one of the key physicochemical properties that is essential to optimise for drug formulation and systemic absorption. While there are several kinetic and thermodynamic solubility assays that can be incorporated into the compound optimisation cascade, it is also useful to employ theoretical calculations for very high-throughput predictions of aqueous solubility. The general solubility equation (GSE), first introduced in the 1980s and later optimised in the early 2000s, uses only 2 parameters (the Celsius melting point and octanol-water partition coefficient) and has been a standard within the pharmaceutical industry. This validation paper from 2001 compares the use of the GSE with a Monte Carlo simulation method on 150 compounds and determines that, on average, the GSE provides solubility predictions closer to experimental values. Considering the speed at which the GSE can be applied compared to Monte Carlo simulations, this highlights the usefulness of the simple equation for guiding compound design.

Prediction of Drug Solubility by the General Solubility Equation (GSE).

Chem. Inf. Comput. Sci. 2001, 41, 2, 354–357

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BucketListPapers 59/100: How can computational chemists make real impact in drug discovery?

Fig2 WhatWorksWhatDoesnt

In this report from 2006, Martin assesses how computational chemists can positively impact drug hunting projects by forming close collaborations with medicinal chemists. The report starts by summarising the computational calculations that were the most popular with Abbott medicinal chemists at the time and showed data that indicated how computationally cataloguing structural alerts as SMARTS reduced the number of flagged compounds within Abbott’s compound library over time. Furthermore, several examples were identified where models with low predictability were still deemed useful. For example, log P predictors were shown to have low accuracy but considered to be “good enough” by medicinal chemists to predict relative log P values within a series. The report also highlights examples where computational chemists offered useful insight that aided decision-making, even when the data or models were inaccurate. An example of this was the observation by a computational chemist that the available data for modelling a compound series had a narrow log P range, which led to the prioritisation of more polar compounds that were subsequently optimised into a lead.

In summary, this report is still an important read for computational and medicinal chemists who work together today, serving as a reminder that drug discovery projects benefit when knowledge and insight is shared between the two fields.

What Works and What Does Not: Lessons From Experience in a Pharmaceutical Company

QSAR & Combinatorial Science, 2006, 25, 1192-1200.

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BucketListPapers 58/100: Time for some Skepticism!

Fig3 Healthy skeptism

“Although the development of computational models to aid drug discovery has become an integral part of pharmaceutical research, the application of these models often fails to produce the expected impact on productivity.” The first line of the abstract of this paper introduces the subject and problem succinctly. This important paper covers into the reasons for this lack of success and covers some critical ground on assessing models and incorporating them into med chem workflows in a timely manner. The paper is on the heavy side of statistics but the charts in Fig. 3 should prove useful for assessing models. Following this paper a blog entry from Pat Walter was published online – this is well worth a read too.

Healthy skepticism: assessing realistic model performance

Drug Disco.Today, 2009, 14, 420-427

Here is a follow up blog that is well worth a read:


BucketListPapers 57/100: Are we as smart and consistent as we think we are?

how chemists choose compounds

These two papers should really make you think. First, in 2004 Pharmacia, submitted lists of compounds to their medicinal chemists to select as part of a compound acquisition initiative. By sending multiple lists (rather than one big list) it was possible to look at the consistency of the chemists in their selection choices. While the authors expected a difference between chemists, they did not expect an individual chemist to be inconsistent between each list. This is food for thought. In Novartis in 2012 sent multiple lists of compounds, but in addition the chemists were asked on what criteria they had chosen the compounds i.e. lipophilicity, size, diversity, novelty. The expectation was that calculations and filters would be applied to reduce the lists to a smaller sets to review by eye. From the returned selections it was possible to look at the spread of these properties. The actual selections did not reflect the criteria the chemists had said they used. Of most concern, nearly all chemists said they used novelty as a select, but only 2 of the 19 actually selected novel compounds. Overall, both studies showed considerable bias in compound selection, again considerable food for thought.

Assessment of the Consistency of Medicinal Chemists in Reviewing Sets of Compounds. J. Med. Chem. 2004, 47, 20, 4891–4896 

Inside the Mind of a Medicinal Chemist: The Role of Human Bias in Compound Prioritization during Drug Discovery. PLoS ONE 7(11): e48476.


BucketListPapers 56/100: How have acids and bases faired in drug discovery?

acids and base in drugs solubility

“It is fairly common for drugs to be classified as weak acids or bases or perhaps more accurately as acids, bases, neutral, or zwitterionic.” Often the acidic or basic group is key part of the pharmacophore, and as such tend not be optimised by fine tuning the pKa. This very useful review is a comprehensive study of the effect acidic and basic compounds.  Table 1 to 4 should be printed out by any compound designing chemists, and carried around as a reference. These summaries the effect on ADMET properties of ionised molecules from several dozen papers. The selected plot above (Figure 5) showing the clear effect of having ionisable group on aqueous solubility.  However, having read the rest of the paper you will be left with the view that having a neutral compound as a drug is the best outcome, given that both lipophiliic acids and bases tend to have some kind of ADMET issue.

Acidic and Basic Drugs in Medicinal Chemistry: A Perspective J. Med. Chem. 2014, 57, 23, 9701–9717

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BucketListPapers 55/100: Methyl, Ethyl, Futile – We have all said it…

We distinctly remember when this paper came out, and it was not long after that the phrase entered the common lexicon of the medicinal chemists. The study was not that many years after the Rule-of-Five paper, and within our discipline, the naughties become a decade of looking at compounds and defining further guidelines (some becoming un-useful “rules”). This is a must read, as it discuss the key principal of finding the lipophilicity ‘sweet spot’. This is where binding affinity and absorption are sufficient, but not too high, where metabolism and safety concerns arise. The reason for “methyl, ethyl, futile” phrase is simple because it is too easy to increase the lipophilicity of a compound series and “potency” improves, leading to a false sense of progress on a project. Later on came the concept of efficiency in drug design; getting the most out of each atom and lipophilic group. Read the paper and it will improve your thinking in compound design.

Lipophilicity in PK design: methyl, ethyl, futile.   J Comput Aided Mol Des. 2001 Mar;15(3):273-86. 

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BucketListPapers 54/100: The biggest screening libraries ever made: DELs

Picture BLP 54 100

The last post concerned fragment libraries – round built on the philosophy “small fragments can represent massive libraries” at the other end of the scale are DNA encoded combinatorial libraries (DELs).  DELs represent the technological offspring of combinatorial chemistry and molecular biology with a little classical protein biochemistry for good measure. With split pool synthesis to make vast libraries and encoding the sequence of chemistry used in a DNA sequence attached to the compounds, huge libraries can be made and potent ligands identified.  Chromatography with the protein target as ‘bait’ to fish out the most potent compounds followed by PCR to sequence the DNA tag establishes the identity of the best binders.  If you can do affinity chromatography with your protein target, DELs represent the other extreme approach to lead generation.  The first paper is a pure classic – Brenner and Lerner’s PNAS publication contains the essence of the technique in highly readable form.  It contains the brilliant line “we recently, in principle, solved the synthetic procedure for peptides”.   But actually to industrialise takes another 17 years.  There has been a huge number of synthetic chemistry devils to outwit in making the method scalable and Morgan et al’s 2009 paper shows one version of the production and screening of billion compound libraries and the identification of inhibitors reduced to practice.

“Encoded combinatorial chemistry”, Brenner and Lerner,  Proc. Natl. Acad. Sci (1992), 89, 5381-5383

“Design, synthesis and selection of DNA-encoded small-molecule libraries”, Morgan et al, Nature Chem. Bio. (2009), 5, 647 – 654

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