title: Discovery and structure-activity relationships of piperidinone- and piperidine-constrained phenethylamines as novel, potent, and selective dipeptidyl peptidase IV inhibitors.
abstract: Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
authors: Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. zhonghua.pei@abbott.com
authors: Zhonghua
authors: Z
authors: Pei
authors: Xiaofeng
authors: X
authors: Li
authors: Thomas W
authors: TW
authors: von Geldern
authors: Kenton
authors: K
authors: Longenecker
authors: Daisy
authors: D
authors: Pireh
authors: Kent D
authors: KD
authors: Stewart
authors: Bradley J
authors: BJ
authors: Backes
authors: Chunqiu
authors: C
authors: Lai
authors: Thomas H
authors: TH
authors: Lubben
authors: Stephen J
authors: SJ
authors: Ballaron
authors: David W A
authors: DW
authors: Beno
authors: Anita J
authors: AJ
authors: Kempf-Grote
authors: Hing L
authors: HL
authors: Sham
authors: James M
authors: JM
authors: Trevillyan
mesh_terms: D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008968:Molecular Conformation; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010881:Piperidones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D058892:Adenosine Deaminase Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D010627:Phenethylamines; D010880:Piperidines; D010881:Piperidones; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4