title: Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series.
abstract: The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA. Electronic address: shan@arenapharm.com.
authors.forename: Sangdon
authors.initials: S
authors.lastname: Han
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Sanju
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Imelda
authors.initials: I
authors.lastname: Calderon
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kawasaki
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Yue
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Juerg
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Wong
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Buzard
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Carroll
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Chu
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Hussein
authors.initials: H
authors.lastname: Al-Sharmma
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Hsin-Hui
authors.initials: HH
authors.lastname: Shu
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Tung
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Unett
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Behan
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Yoon
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Khawja A
authors.initials: KA
authors.lastname: Usmani
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Chen
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Abu
authors.initials: A
authors.lastname: Sadeque
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Leonard
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003510:Cyclohexanes / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D003510:Cyclohexanes; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled
keywords: GDIR; GPR119 agonist; T2DM; Trans-1,4-dioxycyclohexane