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Title: 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
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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
Citation Metrics:
Cited by: 24 works
Citation information provided by
Web of Science

References (13)

Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes journal January 2008
Discovery of Potent and Selective Dipeptidyl Peptidase IV Inhibitors Derived from β-Aminoamides Bearing Subsituted Triazolopiperazines journal January 2008
Omarigliptin (MK-3102): A Novel Long-Acting DPP-4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes journal April 2014
Discovery of Alogliptin:  A Potent, Selective, Bioavailable, and Efficacious Inhibitor of Dipeptidyl Peptidase IV † journal May 2007
8-(3-( R )-Aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a Highly Potent, Selective, Long-Acting, and Orally Bioavailable DPP-4 Inhibitor for the Treatment of Type 2 Diabetes † journal December 2007
9-Benzyl-6-(dimethylamino)-9H-purines with antirhinovirus activity journal October 1988
Addition of Amines to Nitriles Catalyzed by Ytterbium Amides:  An Efficient One-Step Synthesis of Monosubstituted N -Arylamidines journal February 2008
A short, versatile synthesis of porphobilinogen journal January 1976
Prolyl peptidases: a serine protease subfamily with high potential for drug discovery journal August 2003
Purification, identification and characterisation of seprase from bovine serum journal November 2004
Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8: A novel dipeptidyl peptidase journal October 2000
Identification and characterization of human DPP9 , a novel homologue of dipeptidyl peptidase IV journal October 2002
Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. journal June 1994

Cited By (4)

Emergence of promising novel DPP-4 inhibitory heterocycles as anti-diabetic agents: A review journal June 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
Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening journal April 2018
Gold Nanoparticle-Based Colorimetric and Electrochemical Methods for Dipeptidyl Peptidase-IV Activity Assay and Inhibitor Screening journal October 2016

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

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