The Merck CETP inhibitor backup, MK-8262 , is potential best-in-class CETP inhibitor, which was only discontinued as a backup due to the success of its predecessor, anacetrapib in Ph. III. Reviewer Kim Huard thought this CETP inhibitor was a great piece of work from Merck, and is a great example how to deal with a very lipophilic binding site [...]

Acoramidis (AG10), an oral, second-generation stabilizer of the tetrameric transthyretin (TTR) protein, was submitted for FDA approval on Dec. 5, 2023 by BridgeBio for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). The rare but potentially fatal disease is characterized by amyloid deposits in heart muscle. The molecule has the potential to be best-in-class relative to Pfizer’s $2.4B+/yr blockbuster tafamidis. This story highlights early experiments validating TTR stabilization, why enthalpy of binding was key, how it binds TTR, its 30-mo clinical data, and more.

Recently, a surge of (pre)clinical compounds inhibiting the NLRP3 inflammasome, often featuring a hexahydroindacene ring system, has emerged, including Nodthera’s ND-0796. In a push for new chemotypes, AZ and Mitsubishi Tanabe have disclosed their clinical compound, AZD4144, which is currently in Ph. I trials in healthy volunteers. The discovery story detailed their efforts to overcome PLD (phospholipidosis), genotoxicity, and hERG inhibition in a non-classical pharmacophore series. The discovery was presented by Anders Johansson at the EFMC-ISMC 2024 Meeting in Rome.

The Cytokinetics next-generation myosin inhibitor, aficamten , is a phase II candidate for genetic hypertrophic cardiomyopathies, and is orally dosed between 5-30 mg QD. It follows BMS’s mavacamten ( acquired from Myokardia in a $13.1B deal), whose NDA is under review by the FDA. This class of molecules is intended to address hypertrophic [...]

Nerandomilast (BI 1015550) is Boehringer Ingelheim’s PDE4B inhibitor with demonstrated clinical potential in treating IPF.