Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators
Med. Chem.2024, 67, 14432-14442
Coenzyme A (CoA) is a thiol cofactor that carries carboxylic acid substrates to where they are needed in important metabolic pathways, such as the Citric Acid Cycle. CoA is biosynthesised from pantothenic acid (Vitamin B5). The first and rate-limiting step of this synthesis is phosphorylation of pantothenic acid by pantothenate kinase (PANK) using a molecule of ATP. Mutations in the PANK gene thus cause CoA deficiencies which can lead to an awful childhood-onset neurological condition known as Pantothenate Kinase Associated Neurodegeneration (PKAN), patients of which currently have limited treatment options available.
In this paper, a team based at St Jude Children’s Research Hospital in Memphis, TN, present their lead optimisation story on a series of simple pyridazine compounds previously found to activate PANK3, increase CoA levels in mouse brain tissue and even show efficacy in an in-vivo mouse model for PKAN. The optimisation goal was centred around improving the physicochemical properties of the series while maintaining its CoA-boosting ability, leading to longer in-vivo t1/2 and improved overall exposure. Liabilities such as poor solubility and rapid glutathione (GSH) conjugation were identified as weaknesses.
The assay results on which key decisions were made included: the cellular CoA level elevation, microsomal stability and solubility. Interestingly, the authors were looking for intermediate potency (2- 20 nM IC50: PANK3) compounds rather than high potency (<2 nM IC50: PANK3) compounds, as the latter were found to become orthosteric inhibitors of PANK3, rather than allosteric activators, leading to lower CoA levels in the cell assay. This effect might be demonstrated in two examples shown in this publication, compounds 1 and 4 (Fig. 1, above), where, the latter has a ~10x lower IC50 than 1, but also has a diminished effect on CoA elevation. Its not every day that you optimise the IC50 value to be within a window, rather than as low as the assay will allow!
Classic lead optimisation moves were made until a small number were taken forward for PK studies, where a good in-vitro-in-vivo correlation (IVIVC) was found with their microsomal stability measurements, indicating a primarily Phase I metabolism method of elimination. Using a regime derived from PK-PD relationships already established in their earlier work, they measured the CoA level elevation in lung and brain tissue after dosing their lead compounds, confirming an improved candidate profile. The best was advanced into clinical trials in collaboration with BridgeBio Pharma as BBP-671. It will be an interesting one to watch as further applications for CoA-boosting agents are discovered, for the treatment of other conditions.