title: Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists.
abstract: Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ⩾10 mg/kg.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States. Electronic address: mazimioara@gnf.org.
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: 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: 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: Gerald
authors.initials: G
authors.lastname: Lelais
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
authors.forename: John
authors.initials: J
authors.lastname: Mecom
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: McNeill
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: Groessl
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; D055808:Drug Discovery; D051379:Mice; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C519854:GPR119 protein, human; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; C030986:pyrimidine
keywords: GPCR agonists; GPR119; Tricyclic pyrazolopyrimidines; Type 2 diabetes