“compound 23” is an oral, selective Factor XIa inhibitor intended as an anticoagulation agent. Since the clinical translatability of FXIa inhibition in preclinical models hasn’t been established, this program was driven by activity in in vitro human plasma coagulation assays. The team was able to turn a 0.6 uM hit originally from a complement [...]

The BMS factor XIa inhibitor, milvexian (BMS-986177), is an oral antithrombotic with a Ki of 0.11 nM. A member of this macrocyclic series was previously highlighted as one of 2020’s Molecules of the Year . Poor pharmaceutic properties from previous preclinical molecules such as solubility were addressed resulting in this candidate. Milvexian [...]

The Sanofi S1P1 agonist, SAR247799 , is a biased agonist of the S1P1 sphingosine receptor, preferentially activating G-protein signaling over the β-arrestin and internalization pathways. Commercial S1P1 modulators such as fingolimod and ozanimod exert their immunosuppressive effects in multiple sclerosis and other diseases primarily by [...]

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 [...]

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.