title: AMG 837: a novel GPR40/FFA1 agonist that enhances insulin secretion and lowers glucose levels in rodents.
abstract: Agonists of GPR40 (FFA1) have been proposed as a means to treat type 2 diabetes. Through lead optimization of a high throughput screening hit, we have identified a novel GPR40 agonist called AMG 837. The objective of these studies was to understand the preclinical pharmacological properties of AMG 837. The activity of AMG 837 on GPR40 was characterized through GTPγS binding, inositol phosphate accumulation and Ca(2+) flux assays. Activity of AMG 837 on insulin release was assessed on isolated primary mouse islets. To determine the anti-diabetic activity of AMG 837 in vivo, we tested AMG 837 using a glucose tolerance test in normal Sprague-Dawley rats and obese Zucker fatty rats. AMG 837 was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo. Acute administration of AMG 837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing of AMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG 837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. These studies support the potential utility of AMG 837 for the treatment of type 2 diabetes.
authors.affiliation: Metabolic Disorders, Amgen Inc., South San Francisco, California, United States of America. dclin@amgen.com
authors.forename: Daniel C-H
authors.initials: DC
authors.lastname: Lin
authors.forename: Jane
authors.initials: J
authors.lastname: Zhang
authors.forename: Run
authors.initials: R
authors.lastname: Zhuang
authors.forename: Frank
authors.initials: F
authors.lastname: Li
authors.forename: Kathy
authors.initials: K
authors.lastname: Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Chen
authors.forename: Thanhvien
authors.initials: T
authors.lastname: Tran
authors.forename: Edwin
authors.initials: E
authors.lastname: Lopez
authors.forename: Jenny Ying Lin
authors.initials: JY
authors.lastname: Lu
authors.forename: Xiaoyan Nina
authors.initials: XN
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: George R
authors.initials: GR
authors.lastname: Tonn
authors.forename: Gayathri
authors.initials: G
authors.lastname: Swaminath
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Reagan
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.forename: Yi-Jyun
authors.initials: YJ
authors.lastname: Lin
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Houze
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000819:agonists / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D019518:Postprandial Period / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000480:Alkynes; D010666:Phenylpropionates
chemical_list: D001713:Biphenyl Compounds; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; C473036:Ffar1 protein, mouse; C557933:AMG-837; D000480:Alkynes; D010666:Phenylpropionates
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