Despite the remarkable emergence of HAART in the 1990s, the fight against HIV infection is by no means finished. At the ACS Fall 2024 meeting in Denver, CO, Gilead Sciences presented the structure and discovery story of elunonavir (GS-1156), a novel HIV protease inhibitor with remarkable metabolic stability and a human half-life exceeding two weeks. Based on BMS’ atazanavir, the compound incorporates structural elements inspired by Gilead’s HCV NS5A inhibitor program which led to ledipasvir, as “stabilizer” motifs to avoid the extensive CYP metabolism seen in current inhibitors.

EOS-984 is an oral, potential first-in-class, highly selective ENT1 inhibitor from iTeos currently in clinical trials for advanced solid tumors. The drug, which was identified through SBDD and optimization of the vasodilator dilazep, targets the immunosuppressive effects of adenosine, which helps tumors evade immune detection. This is an excellent case study on the importance of understanding a molecule's bioactive conformation to reduce the entropy of binding and enhance potency.

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.

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.

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.