Your browser doesn't support javascript.
loading
Improved Cav2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide.
Shao, Pengcheng P; Ye, Feng; Chakravarty, Prasun K; Herrington, James B; Dai, Ge; Bugianesi, Randal M; Haedo, Rodolfo J; Swensen, Andrew M; Warren, Vivien A; Smith, McHardy M; Garcia, Maria L; McManus, Owen B; Lyons, Kathryn A; Li, Xiaohua; Green, Mitchell; Jochnowitz, Nina; McGowan, Erin; Mistry, Shruti; Sun, Shu-Yu; Abbadie, Catherine; Kaczorowski, Gregory J; Duffy, Joseph L.
Afiliación
  • Shao PP; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Ye F; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Chakravarty PK; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Herrington JB; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Dai G; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Bugianesi RM; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Haedo RJ; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Swensen AM; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Warren VA; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Smith MM; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Garcia ML; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • McManus OB; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Lyons KA; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Li X; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Green M; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Jochnowitz N; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • McGowan E; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Mistry S; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Sun SY; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Abbadie C; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Kaczorowski GJ; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Duffy JL; Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
ACS Med Chem Lett ; 4(11): 1064-8, 2013 Nov 14.
Article en En | MEDLINE | ID: mdl-24900606
ABSTRACT
We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.
Palabras clave
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos