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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
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  1. Merck Research Lab., Kenilworth, NJ (United States). Dept. of Lead Optimization Chemistry
  2. Merck Research Lab., Kenilworth, NJ (United States). Dept. of Structural Chemistry
  3. Merck Research Lab., Kenilworth, NJ (United States). Dept. of Structural Chemistry
  4. Merck Research Lab., Kenilworth, NJ (United States). Dept. of Department of Pharmacology
  5. Merck Research Lab., Kenilworth, NJ (United States). Dept. of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
+ Show Author Affiliations
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 (US). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE
OSTI ID:
1404985
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 5 Vol. 7; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (4)

Gold Nanoparticle-Based Colorimetric and Electrochemical Methods for Dipeptidyl Peptidase-IV Activity Assay and Inhibitor Screening journal October 2016
Emergence of promising novel DPP-4 inhibitory heterocycles as anti-diabetic agents: A review journal June 2018
Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening journal April 2018
Palladium nanodendrites uniformly deposited on the surface of polymers as an efficient and recyclable catalyst for direct drug modification via Z -selective semihydrogenation of alkynes journal January 2018

Figures / Tables (8)

Figure 1(p. 5)figure Figure 1
Figure 2(p. 6)figure Figure 2
Scheme 1(p. 6)figure Scheme 1
Scheme 2(p. 8)figure Scheme 2
Table 1(p. 9)table Table 1
Figure 3(p. 10)figure Figure 3
Figure 4(p. 10)figure Figure 4
Figure 5(p. 11)figure Figure 5

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Carbohydrates
Diabetes
Inhibition
Inhibitors
OGTT
Redox reactions
Scaffolds
crystal structure
dipeptidyl peptidase IV (DPP-4)
inhibitor tricyclic heterocycles