title: Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists.
abstract: Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of 16, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that 16 could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5.
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Piotrowski
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Futatsugi
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Warmus
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Suvi T M
authors.initials: ST
authors.lastname: Orr
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Freeman-Cook
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Allyn T
authors.initials: AT
authors.lastname: Londregan
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Wei
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Jennings
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Herr
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Coffey
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Jiao
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Storer
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Sophie Y
authors.initials: SY
authors.lastname: Lavergne
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Chin
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Hadcock
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Brenner
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Wolford
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Janssen
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Roush
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Joanne
authors.initials: J
authors.lastname: Buxton
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Terri
authors.initials: T
authors.lastname: Hinchey
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Declan A
authors.initials: DA
authors.lastname: Flynn
keywords: GLP-1; GPCR; TGR5; agonist; diabetes