Context. GCC5694A (GC Pharma (Green Cross)) is an oral SGLT2 inhibitor. SGLT2 inhibitors help glycemic control in diabetes by preventing reabsorption of glucose in the kidney. Dapagliflozin was the first SGLT2 inhibitor approved in the EU (2012), and canagliflozin was the first to be approved in the US (2013). We recently highlighted [...]

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.

PF-05221304 is a liver targeted inhibitor of acetyl-CoA carboxylase (ACC). ACC is a key regulator of lipid metabolism, and there has been significant interest in ACC inhibitors for the treatment of multiple indications including NASH and diabetes. Pfizer previously took a systemic ACC inhibitor into the clinic (PF-05175157), which was found [...]

Peptidic GLP-1R agonists have received significant media coverage over the past year. Shortages of the semaglutide-based injectable diabetes medication Ozempic, which accounts for 40% of GLP-1R agonist US market share, have even emerged, driven by overwhelming demand for the weight loss formulation Wegovy, both for treatment of obesity and for short-term weight loss popularized by celebrities on social media. This article reviews the science of danuglipron, recent news, and what makes it different.

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.