title: Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists.
abstract: The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels.
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Peukert
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Hughes
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jill
authors.initials: J
authors.lastname: Nunez
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Guo
authors.initials: G
authors.lastname: He
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Rishi
authors.initials: R
authors.lastname: Jain
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Luis
authors.initials: L
authors.lastname: Llamas
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Luchansky
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Carlson
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Guiqing
authors.initials: G
authors.lastname: Liang
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Vidya
authors.initials: V
authors.lastname: Kunjathoor
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Pietropaolo
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Shapiro
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Anja
authors.initials: A
authors.lastname: Castellana
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
authors.affiliation: Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Avirup
authors.initials: A
authors.lastname: Bose
keywords: GLP-1 secretion; GPR39 agonists; GPR39 receptor; Zn2+-sensing receptor; antidiabetic treatment; insulin secretion; β-cell protection