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 [...]

NT-0796 is NodThera's pro-drug inhibitor of the NLRP3 inflammasome. NT-0796 is currently in a Ph. Ib/IIa trial in obese individuals at risk of developing atherosclerotic cardiovascular diseases. NT-0796 has the potential to reduce neuroinflammation in Parkinson’s disease. The NLRP3 inflammasome has emerged as a hot target due to its connection to Alzheimer’s disease, Parkinson’s disease, gout, and other diseases. Here is a detailed review of the role of NLRP3 inhibition in treating atherosclerosis, how NT-0796 was identified, and what makes it special, clinical development, 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 [...]

Context. Lenrispodun (Intra-Cellular Therapies) is a phosphodiesterase (PDE) type 1 (PDE1) inhibitor being developed for CNS and non-CNS disorders, including heart failure, and cancer. Studies to identify PDE inhibitors date back at least 30 years, and at least 10 drugs have been approved targeting other PDE proteins (spearheaded by the PDE5 [...]

BridgeBio’s acoramidis (Attruby), an oral, second-generation stabilizer of the TTR protein, has been approved by the FDA for the treatment of ATTR-CM (transthyretin amyloid cardiomyopathy). Amyloid deposits in the heart muscle characterize the rare but potentially fatal disease. This case study reviews the history of TTR modulation, early experiments validating the therapeutic potential of TTR stabilization, the binding mechanism of acoramidis to TTR, the importance of binding enthalpy for differentiation, and the molecule’s impressive 30-month clinical data following an early scare.