title: Discovery of the oxazabicyclo[3.3.1]nonane derivatives as potent and orally active GPR119 agonists.
abstract: The design and synthesis of two conformationally restricted oxazabicyclo octane derivatives as GRP119 agonists is described. Derivatives of scaffold C, with syn configuration, have the best overall profiles with respect to solubility and in vivo efficacy. Compound 25a was found to have extremely potent agonistic activity and was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test at a dose of 0.1 mg/kg.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Xing
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stamford
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Bernard
authors.initials: B
authors.lastname: Neustadt
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Biology, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Tim
authors.initials: T
authors.lastname: Kowalski
authors.affiliation: Department of Biology, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Hawes
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biology, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Hana
authors.initials: H
authors.lastname: Baker
authors.affiliation: Department of Biology, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Kim
authors.initials: K
authors.lastname: O'Neill
authors.affiliation: Department of Biology, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Morgan
authors.initials: M
authors.lastname: Woods
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Huadong
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: William
authors.initials: W
authors.lastname: Greenlee
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D012995:Solubility
chemical_list: D053961:Azabicyclo Compounds; C519854:GPR119 protein, human; C516207:Gpr119 protein, mouse; D007004:Hypoglycemic Agents; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled
keywords: Bridged piperidine; GPR119 agonist; Glucose-dependent insulin secretion; Type 2 diabetes