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Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia.
Palani, Anandan; Rao, Ashwin U; Chen, Xiao; Huang, Xianhai; Su, Jing; Tang, Haiqun; Huang, Ying; Qin, Jun; Xiao, Dong; Degrado, Sylvia; Sofolarides, Michael; Zhu, Xiaohong; Liu, Zhidan; McKittrick, Brian; Zhou, Wei; Aslanian, Robert; Greenlee, William J; Senior, Mary; Cheewatrakoolpong, Boonlert; Zhang, Hongtao; Farley, Constance; Cook, John; Kurowski, Stan; Li, Qiu; van Heek, Margaret; Wang, Gangfeng; Hsieh, Yunsheng; Li, Fangbiao; Greenfeder, Scott; Chintala, Madhu.
Afiliación
  • Palani A; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Rao AU; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Chen X; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Huang X; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Su J; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Tang H; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Huang Y; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Qin J; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Xiao D; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Degrado S; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Sofolarides M; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Zhu X; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Liu Z; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • McKittrick B; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Zhou W; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Aslanian R; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Greenlee WJ; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Senior M; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Cheewatrakoolpong B; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Zhang H; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Farley C; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Cook J; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Kurowski S; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Li Q; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • van Heek M; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Wang G; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Hsieh Y; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Li F; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Greenfeder S; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Chintala M; Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
ACS Med Chem Lett ; 3(1): 63-8, 2012 Jan 12.
Article en En | MEDLINE | ID: mdl-24900372
ABSTRACT
Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (33) with an EC50 of 2 nM in the hu-GPR109a assay. Compound 33 demonstrated good oral bioavailability in all species. Compound 33 exhibited dose-dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.0 mg/kg in fasted male beagle dogs. Compound 33 had no overt signs of flushing at doses up to 10 mg/kg with an improved therapeutic window to flushing as compared to nicotinic acid. Compound 33 was evaluated in human clinical trials.
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Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2012 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2012 Tipo del documento: Article País de afiliación: Estados Unidos