title: Discovery of structurally novel, potent and orally efficacious GPR119 agonists.
abstract: Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantly improved in vitro activity and oral exposure, to elevate GLP1 acutely in an in vivo mouse model at a dose of 10mg/kg.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States. Electronic address: palper@gnf.org.
authors.forename: Phil
authors.initials: P
authors.lastname: Alper
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Mihai
authors.initials: M
authors.lastname: Azimioara
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cow
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mutnick
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Victor
authors.initials: V
authors.lastname: Nikulin
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Michellys
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Esther
authors.initials: E
authors.lastname: Reding
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Paliotti
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Dingjiu
authors.initials: D
authors.lastname: Bao
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Zoll
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Young
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zimmerman
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Groessel
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Sean B
authors.initials: SB
authors.lastname: Joseph
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: McNamara
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States. Electronic address: repple@gnf.org.
authors.forename: Robert
authors.initials: R
authors.lastname: Epple
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C519854:GPR119 protein, human; C516207:Gpr119 protein, mouse; D007004:Hypoglycemic Agents; D011720:Pyrazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled
keywords: GPCR agonists; GPR119; Pyrazolopyrimidines; Type 2 diabetes