title: Indazole-6-phenylcyclopropylcarboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy.
abstract: GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: William
authors.identifier: 0000-0002-2977-1744
authors.initials: W
authors.lastname: McCoull
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bailey
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Peter
authors.initials: P
authors.lastname: Barton
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Birch
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Alastair J H
authors.initials: AJ
authors.lastname: Brown
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Butler
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Scott
authors.initials: S
authors.lastname: Boyd
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Butlin
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Ben
authors.initials: B
authors.lastname: Chappell
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Clarkson
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Shelley
authors.initials: S
authors.lastname: Collins
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Robert M D
authors.initials: RM
authors.lastname: Davies
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Anne
authors.initials: A
authors.lastname: Ertan
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Clare D
authors.initials: CD
authors.lastname: Hammond
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Holmes
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Carol
authors.initials: C
authors.lastname: Lenaghan
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Anita
authors.initials: A
authors.lastname: Midha
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Pablo
authors.initials: P
authors.lastname: Morentin-Gutierrez
authors.affiliation: IMED CVMD, AstraZeneca , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Moore
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Piotr
authors.initials: P
authors.lastname: Raubo
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Graeme
authors.initials: G
authors.lastname: Robb
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002264:Carboxylic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: D001786:Blood Glucose; D002264:Carboxylic Acids; C519853:FFAR4 protein, human; C498007:FFAR4 protein, mouse; D007191:Indazoles; D043562:Receptors, G-Protein-Coupled