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.
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