title: Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists.
abstract: A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor.
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States. Electronic address: dbuzard@arenapharm.com.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Buzard
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Juerg
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Sangdon
authors.initials: S
authors.lastname: Han
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Imelda
authors.initials: I
authors.lastname: Calderon
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Wong
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kawasaki
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Sanju
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bhat
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Tawfik
authors.initials: T
authors.lastname: Gharbaoui
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Luis
authors.initials: L
authors.lastname: Lopez
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Dawei
authors.initials: D
authors.lastname: Yue
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Whelan
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Hussien
authors.initials: H
authors.lastname: Al-Shamma
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Unett
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Hsin-Hui
authors.initials: HH
authors.lastname: Shu
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Tung
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Chang
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Ching-Fen
authors.initials: CF
authors.lastname: Chuang
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Abu
authors.initials: A
authors.lastname: Sadeque
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Chu
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: James N
authors.initials: JN
authors.lastname: Leonard
authors.affiliation: Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C572261:APD597; C519854:GPR119 protein, human; D010880:Piperidines; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled
keywords: APD597; Diabetes; GDIR; GPR119