The Merck bicyclic macrocyclic peptide PCSK9 inhibitor, “ compound 44 ,” is a highly potent (Ki = 0.00239 nM) and orally bioavailable (cyno %F = 2.9, t1/2 = 10 h) agent against a notoriously difficult target for small molecules, demonstrating target engagement comparable to approved PCSK9 antibodies. The discovery of this molecule is an [...]

BI-0115 inhibits the C-type lectin family member lectin-like oxidized LDL-receptor-1 (LOX-1) by stabilizing an inactive tetrameric form of the protein. Interestingly, co-crystollography demonstrates that inter-ligand interactions between two BI-0115 molecules contribute to the dimerization of LOX-1 homodimers.

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 [...]

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.