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.

asundexian (BAY2433334) is a reversible Factor XIa active site inhibitor previously disclosed at the 2021 EFMC-ISMC conference . This article highlights the Ph. I data of asundexian in healthy volunteers, showing that the drug is well tolerated, with no clinically relevant bleeding-related adverse events or any relevant CYP3A4 modulation. The [...]

Pfizer disclosed the structure and discovery of their oral small molecule BDK inhibitor/degrader, PF-07328948, during the ACS Fall 2024 First-Time Disclosures session in Denver. The team identified a thiophene carboxylic acid-based hit targeting an allosteric pocket on BDK. Through optimization, they overcame challenges such as potential IADRs and BDK-E2 complex stabilization. By manipulating the dihedral angle of the methoxy group, they enhanced binding interactions, verifying PF-07328948's unexpected mechanism of action in vivo. PF-07328948 is currently Ph. I trials.

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 [...]

BMS-986235/LAR-1219 is an FPR1-sparing FPR2-selective agonist intended to help resolve chronic inflammation/promote wound healing to prevent serious complications like heart failure. It’s a very efficient molecule and is orally efficacious in a mouse myocardial infarction model at doses as low as 0.3 mg/pk, despite having 3 N-H donors (urea + [...]