LY3502970
oral non-peptide GLP-1R GPCR partial agonist in Ph. I for Type 2 diabetes, HV study complete from cell-based screen and opt. PNAS, Nov. 11, 2020 Chugai, Shizuoka, JP / Eli Lilly, Indianapolis, IN
Other molecules you may be interested in
aleniglipron
The recently released WHO INN proposed names list includes the structure and name of Structure Therapeutics’ oral small molecule GLP-1R agonist, aleniglipron (GSBR-1290). Seemingly emerging from a “fast-follower” program based on Chugai/Eli Lilly’s orforglipron, the compound includes an unusual phosphine oxide motif and has shown positive results on plasma glucose levels and bodyweight in a Ph. IIa study.
PCO371
Chugai’s PCO371 is an oral, biased agonist and "molecular wedge" of the class B GPCR, PTHR1, that first entered development for hypoparathyroidism in 2015 (NCT02475616). While Class A GPCRs, which typically have compact ligandable pockets are the most common targets for approved drugs, Class B GPCRs like PTHR1, GLP-1R, and CGRP are notoriously difficult to drug since they normally bind large peptides with long transmembrane tunnels that are not easily bound by small molecules. This article explains what makes PCO371 a big deal for GPCR drug discovery.
seladelpar
In August 2024, seladelpar (LivdelziTM) became the first FDA-approved selective agonist of PPARδ (peroxisome proliferator-activated receptor δ), following an almost 20-year journey from the original discovery and patent publications. Originally developed by CymaBay in collaboration with Johnson & Johnson, approval was granted to Gilead Sciences following their February 2024 purchase of CymaBay Therapeutics for $4.3B. Seladelpar was approved as a second-line treatment for patients with primary biliary cholangitis.
orforglipron
Orforglipron is an oral non-peptide glucagon-like peptide-1 (GLP-1) receptor partial agonist that entered Ph. III for obesity and type-2-diabetes mellitus (T2DM). This 2020 and 2023 Molecule of the Year nominee (nominated initially back when it was still in Ph. I) was first discovered by Chugai Pharmaceuticals under the name OWL833, then licensed by Eli Lilly for worldwide development under the name LY3502970. The article discusses where it sits in the GLP-1R agonist landscape, why it’s scientifically notable, how it works with illustrations from cryo-EM structures, its synthesis, and more.
GS-9688 (selgantolimod)
GS-9688 (selgantolimod) is a potent and selective TLR8 agonist sparing related receptor TLR7, and is intended to induce better immune responses in chronic hepatitis B. Since systemic activation of TLR8 was undesirable, selgantolimod was designed to have high first-pass hepatic clearance to induce effective antiviral immunity in the liver but [...]