title: Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit.
abstract: A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
authors.affiliation: Metabolic Disease Research, Abbott Laboratories, Abbott Park Road, Abbott Park, IL 60064-6099, USA. bradley.backes@abbott.com
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Backes
authors.forename: Kenton
authors.initials: K
authors.lastname: Longenecker
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Hamilton
authors.forename: Kent
authors.initials: K
authors.lastname: Stewart
authors.forename: Chunqiu
authors.initials: C
authors.lastname: Lai
authors.forename: Hana
authors.initials: H
authors.lastname: Kopecka
authors.forename: Thomas W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: David J
authors.initials: DJ
authors.lastname: Madar
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lubben
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Zinker
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Tian
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ballaron
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Mika
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Kempf-Grote
authors.forename: Candace
authors.initials: C
authors.lastname: Black-Schaefer
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: James M
authors.initials: JM
authors.lastname: Trevillyan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D053138:Cyclohexenes / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008956:Models, Chemical; D008968:Molecular Conformation; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats
chemical_list: D001786:Blood Glucose; D053138:Cyclohexenes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010627:Phenethylamines; D011759:Pyrrolidines; C052568:cyclohexene; C032519:pyrrolidine