Structure-activity relationships of thiadiazole agonists of the human secretin receptor

• DOI: 10.1016/j.slasd.2024.100176
• Publication Date: 2024-08-08T01:24:41Z
• Authors: Robert Ardecky; Daniela G. Dengler; Kaleeckal G. Hari...; Mathew M. Abelman; Jiwen Zou; Bryan A. Kramer; Santhi Reddy Ganji; Steve Olson; Alina Ly; Nikhil Puvvula; Chen-Ting Ma; Raghuveer Ramacha...; Eduard A. Sergienko; Laurence J. Miller
• Keywords: Secretin; Lead compound; Structure–activity relationship

Agonists of the secretin receptor have potential applications for diseases cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists this been developed. In current work, we identified a new small molecule lead compound with pharmacological profile. We prepared characterized systematic structure-activity series around thiadiazole scaffold to better understand molecular determinants its activity. were able enhance in vitro activity maintain specificity parent compound. found most active candidate be quite stable plasma, although it was metabolized by hepatic microsomes. This chemical probe should useful studies needs tested vivo could an important toward development first-in-class orally agonist receptor, which multiple disease states.