title: Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes.
abstract: A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3-phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA. Electronic address: jonathan_wilson@merck.com.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Wilson
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Kurukulasuriya
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sinz
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lombardo
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Bender
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Dann
authors.initials: D
authors.lastname: Parker
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Sherer
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Costa
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Dingley
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Mitelman
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Tong
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Randal
authors.initials: R
authors.lastname: Bugianesi
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Anka
authors.initials: A
authors.lastname: Ehrhardt
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Priest
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Ratliff
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Feroze
authors.initials: F
authors.lastname: Ujjainwalla
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Nargund
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Edmondson
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005951:Glucose Tolerance Test; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010077:Oxazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000172:deficiency; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C501537:GPR142 protein, human; C511538:GPR142 protein, mouse; D010077:Oxazepines; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C000621327:benzo-(1,2,4)-triazolo-(1,4)-oxazepine
keywords: Diabetes; GPR142; Wild-type knock-out study