title: Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.
abstract: 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.
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Wen-Lian
authors.initials: WL
authors.lastname: Wu
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Domalski
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Burnett
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Pissarnitski
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stamford
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ying-Duo
authors.initials: YD
authors.lastname: Gao
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Aileen
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Terri M
authors.initials: TM
authors.lastname: Kelly
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zuliang
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Powles
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Shiying
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Mei
authors.affiliation: Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Joyce
authors.initials: J
authors.lastname: Hwa
keywords: Diabetes; OGTT; crystal structure; dipeptidyl peptidase IV (DPP-4); inhibitor; tricyclic heterocycles