title: Discovery of phenyl acetamides as potent and selective GPR119 agonists.
abstract: The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: cheng.zhu@merck.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Zack Zhiqiang
authors.initials: ZZ
authors.lastname: Guo
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Szewczyk
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Kang
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Chicchi
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Anka
authors.initials: A
authors.lastname: Ehrhardt
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Woods
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Toru
authors.initials: T
authors.lastname: Seo
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Woods
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: van Heek
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Dingley
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Pang
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Gino M
authors.initials: GM
authors.lastname: Salituro
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Powell
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Terebetski
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Viktor
authors.initials: V
authors.lastname: Hornak
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Orr
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Feroze
authors.initials: F
authors.lastname: Ujjainwalla
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Miller
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stamford
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Harold B
authors.initials: HB
authors.lastname: Wood
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Kowalski
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Edmondson
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D006207:Half-Life; D006801:Humans; D045663:Quantum Dots; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; C519854:GPR119 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: Cis cyclopropane; GPR119 agonist; Glucose dependent insulin secretion; Phenyl acetamide; Type 2 diabetes