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    Molecule

    Chiesi Farmaceutici’s CHF-6523 is an inhaled, lung-restricted, selective PI3Kδ inhibitor designed to provide relief to patients with COPD. Its development involved optimization of permeability and solubility as well as identification of a solid form amenable for dry powder inhalation. Disclosed at the EFMC-ISMC 2024 joint conference in Rome, Italy, this article covers the structure, development, and early clinical data of CHF-6523, which ultimately indicates that PI3Kδ inhibition may not provide clinical effect in reduction of lung inflammation.

    Molecule

    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.

    Molecule

    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.