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Discovery of phenyl acetamides as potent and selective GPR119 agonists.
Zhu, Cheng; Wang, Liping; Zhu, Yuping; Guo, Zack Zhiqiang; Liu, Ping; Hu, Zhiyong; Szewczyk, Jason W; Kang, Ling; Chicchi, Gary; Ehrhardt, Anka; Woods, Andrea; Seo, Toru; Woods, Morgan; van Heek, Margaret; Dingley, Karen H; Pang, Jianmei; Salituro, Gino M; Powell, Joyce; Terebetski, Jenna L; Hornak, Viktor; Campeau, Louis-Charles; Orr, Robert K; Ujjainwalla, Feroze; Miller, Michael; Stamford, Andrew; Wood, Harold B; Kowalski, Timothy; Nargund, Ravi P; Edmondson, Scott D.
Affiliation
  • Zhu C; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: cheng.zhu@merck.com.
  • Wang L; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Zhu Y; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Guo ZZ; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Liu P; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Hu Z; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Szewczyk JW; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Kang L; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Chicchi G; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Ehrhardt A; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Woods A; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Seo T; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Woods M; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • van Heek M; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Dingley KH; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Pang J; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Salituro GM; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Powell J; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Terebetski JL; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Hornak V; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Campeau LC; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Orr RK; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Ujjainwalla F; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Miller M; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Stamford A; Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Wood HB; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Kowalski T; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Nargund RP; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Edmondson SD; Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Bioorg Med Chem Lett ; 27(5): 1124-1128, 2017 03 01.
Article in En | MEDLINE | ID: mdl-28185720
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, G-Protein-Coupled / Acetamides Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2017 Document type: Article Country of publication:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, G-Protein-Coupled / Acetamides Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2017 Document type: Article Country of publication: