title: Design of potent and selective GPR119 agonists for type II diabetes.
abstract: Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC(50)=3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000 Rahway, NJ 07065, USA. jason_szewczyk@merck.com
authors.forename: Jason W
authors.initials: JW
authors.lastname: Szewczyk
authors.forename: John
authors.initials: J
authors.lastname: Acton
authors.forename: Alan D
authors.initials: AD
authors.lastname: Adams
authors.forename: Gary
authors.initials: G
authors.lastname: Chicchi
authors.forename: Stanley
authors.initials: S
authors.lastname: Freeman
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Cai
authors.initials: C
authors.lastname: Li
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: Ralph
authors.initials: R
authors.lastname: Mosely
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
authors.forename: Rachel
authors.initials: R
authors.lastname: Samuel
authors.forename: Conrad
authors.initials: C
authors.lastname: Santini
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kake
authors.initials: K
authors.lastname: Zhao
authors.forename: Harold B
authors.initials: HB
authors.lastname: Wood
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D004988:Ethers, Cyclic / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004988:Ethers, Cyclic; C519854:GPR119 protein, human; D043562:Receptors, G-Protein-Coupled; C043657:cyclopropanol