title: Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin.
abstract: Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Tesfaye_Biftu@merck.com
authors: Tesfaye
authors: T
authors: Biftu
authors: Giovanna
authors: G
authors: Scapin
authors: Suresh
authors: S
authors: Singh
authors: Dennis
authors: D
authors: Feng
authors: Joe W
authors: JW
authors: Becker
authors: George
authors: G
authors: Eiermann
authors: Huaibing
authors: H
authors: He
authors: Kathy
authors: K
authors: Lyons
authors: Sangita
authors: S
authors: Patel
authors: Aleksandr
authors: A
authors: Petrov
authors: Ranabir
authors: R
authors: Sinha-Roy
authors: Bei
authors: B
authors: Zhang
authors: Joseph
authors: J
authors: Wu
authors: Xiaoping
authors: X
authors: Zhang
authors: George A
authors: GA
authors: Doss
authors: Nancy A
authors: NA
authors: Thornberry
authors: Ann E
authors: AE
authors: Weber
mesh_terms: D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003514:Cyclohexylamines / Q000737:chemistry*; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058892:Adenosine Deaminase Inhibitors; D003514:Cyclohexylamines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D017320:HIV Protease Inhibitors; D011719:Pyrazines; D014230:Triazoles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate