Cerevance’s CVN293 is an oral, CNS-penetrant, selective inhibitor of potassium efflux-mediated NLRP3-inflammasome activation in microglia for the treatment of neurodegenerative disorders. Cerevance’s NETSseq platform was used to discover a microglia-specific potassium efflux channel, KCNK13, which allows modulation of the NLRP3-inflammasome in the CNS without affecting peripheral innate immunity. Read the full article to discover highlights on the CNS-penetration of highly polar compounds and how particle size can be key to oral bioavailability

BAY 2413555 is a M2R PAM that has the potential to counter parasympathetic withdrawal and restore autonomic balance in heart failure patients. The preclinical and clinical data of BAY 2413555 showed it has positive effects on heart rate and heart rate variability and a relatively long human t1/2 of 37 h. The Ph. I trial, however, was terminated in March 2024 due to findings from a chronic toxicology study. This article covers the discovery of BAY 2413555, presented by Alexandros Vakalopoulos of Bayer at the EFMC-ISMC 2024 conference in Rome and published in the Journal of Medicinal Chemistry.

STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant PI3Kα (phosphatidylinositol-3 kinase α) targeting a cryptic pocket near the ATP-binding site. PI3Kα plays a central role in many cancers, and has been recently highlighted in coverage of 2021 Molecule of the Year nominee and PI3Kα degrader inavolisib. Currently approved PI3Kα modulators are limited by their off-target activities on WT PI3Kα and other kinases, leading to significant side effects including hyperglycemia and rash.

AZ-PRMT5i-1 is an orally bioavailable MTA-cooperative PRMT5 inhibitor that specifically targets MTAP-deleted cancers and is structurally related to AZ’s clinical candidate, AZ3470. This case study is an excellent example of utilizing bioisosteric replacements for polar guanidine headgroups, rigidifying scaffolds through spirocyclization to reduce rotatable bonds, and leveraging fluorine atoms beyond simply blocking metabolic soft spots.

Novartis' NLRP3 inhibitor, NVP-DFV890, features a unique sulfonimidamide motif designed to reduce hydrolysis relative to traditional sulfonylureas. This potent compound, with promising PK in humans, is advancing through multiple clinical studies, including Ph. II trials for coronary heart disease and knee osteoarthritis. Presented by Angela Mackay at the EFMC-ISMC 2024 joint conference in Rome, this overview covers NVP-DFV890's discovery, as well as its preclinical PK and PD data.