Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP‑4 Inhibitors for the Treatment of Type 2 Diabetes

• Published in: ACS medicinal chemistry letters Vol. 7; no. 5; pp. 498 - 501
• Main Authors: Wu, Wen-Lian, Hao, Jinsong, Domalski, Martin, Burnett, Duane A, Pissarnitski, Dmitri, Zhao, Zhiqiang, Stamford, Andrew, Scapin, Giovanna, Gao, Ying-Duo, Soriano, Aileen, Kelly, Terri M, Yao, Zuliang, Powles, Mary Ann, Chen, Shiying, Mei, Hong, Hwa, Joyce
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.05.2016; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: 60 APPLIED LIFE SCIENCES; Carbohydrates; Chemistry, Medicinal; crystal structure; Diabetes; dipeptidyl peptidase IV (DPP-4); Inhibition; inhibitor tricyclic heterocycles; Inhibitors; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Letter; Life Sciences & Biomedicine; OGTT; Pharmacology & Pharmacy; Redox reactions; Scaffolds; Science & Technology; crystal structure; Diabetes; inhibitor; dipeptidyl peptidase IV (DPP-4); OGTT; tricyclic heterocycles; DIPEPTIDYL-PEPTIDASE-IV; CLONING; HOMOLOG; IDENTIFICATION
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.6b00027

In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.