Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes
Journal Article
·
· ACS Medicinal Chemistry Letters
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Lead Optimization Chemistry
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Structural Chemistry
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Structural Chemistry
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Department of Pharmacology
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
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.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1404985
- Journal Information:
- ACS Medicinal Chemistry Letters, Vol. 7, Issue 5; ISSN 1948-5875
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Cited by: 24 works
Citation information provided by
Web of Science
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