title: Discovery of a nortropanol derivative as a potent and orally active GPR119 agonist for type 2 diabetes.
abstract: The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. yan.xia@merck.com
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Charles
authors.initials: C
authors.lastname: Jayne
authors.forename: Bernard
authors.initials: B
authors.lastname: Neustadt
authors.forename: Andrew
authors.initials: A
authors.lastname: Stamford
authors.forename: Henry
authors.initials: H
authors.lastname: Vaccaro
authors.forename: Xiaoying Lucy
authors.initials: XL
authors.lastname: Xu
authors.forename: Hana
authors.initials: H
authors.lastname: Baker
authors.forename: Kim
authors.initials: K
authors.lastname: O'Neill
authors.forename: Morgan
authors.initials: M
authors.lastname: Woods
authors.forename: Brian
authors.initials: B
authors.lastname: Hawes
authors.forename: Tim
authors.initials: T
authors.lastname: Kowalski
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D055808:Drug Discovery; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D051379:Mice; D009662:Nortropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: C532423:GPR119 protein, rat; D009662:Nortropanes; D043562:Receptors, G-Protein-Coupled