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Discovery of Acyl-sulfonamide Nav1.7 Inhibitors GDC-0276 and GDC-0310.
Safina, Brian S; McKerrall, Steven J; Sun, Shaoyi; Chen, Chien-An; Chowdhury, Sultan; Jia, Qi; Li, Jun; Zenova, Alla Y; Andrez, Jean-Christophe; Bankar, Girish; Bergeron, Philippe; Chang, Jae H; Chang, Elaine; Chen, Jun; Dean, Richard; Decker, Shannon M; DiPasquale, Antonio; Focken, Thilo; Hemeon, Ivan; Khakh, Kuldip; Kim, Amy; Kwan, Rainbow; Lindgren, Andrea; Lin, Sophia; Maher, Jonathan; Mezeyova, Janette; Misner, Dinah; Nelkenbrecher, Karen; Pang, Jodie; Reese, Rebecca; Shields, Shannon D; Sojo, Luis; Sheng, Tao; Verschoof, Henry; Waldbrook, Matthew; Wilson, Michael S; Xie, Zhiwei; Young, Clint; Zabka, Tanja S; Hackos, David H; Ortwine, Daniel F; White, Andrew D; Johnson, J P; Robinette, C Lee; Dehnhardt, Christoph M; Cohen, Charles J; Sutherlin, Daniel P.
Afiliación
  • Safina BS; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • McKerrall SJ; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Sun S; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Chen CA; Chempartner, Building No. 5, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, P.R. China.
  • Chowdhury S; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Jia Q; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Li J; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Zenova AY; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Andrez JC; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Bankar G; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Bergeron P; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Chang JH; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Chang E; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Chen J; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Dean R; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Decker SM; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • DiPasquale A; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Focken T; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Hemeon I; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Khakh K; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Kim A; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Kwan R; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Lindgren A; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Lin S; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Maher J; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Mezeyova J; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Misner D; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Nelkenbrecher K; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Pang J; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Reese R; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Shields SD; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Sojo L; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Sheng T; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Verschoof H; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Waldbrook M; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Wilson MS; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Xie Z; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Young C; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Zabka TS; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Hackos DH; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • Ortwine DF; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • White AD; Chempartner, Building No. 5, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, P.R. China.
  • Johnson JP; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Robinette CL; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Dehnhardt CM; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Cohen CJ; Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • Sutherlin DP; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
J Med Chem ; 64(6): 2953-2966, 2021 03 25.
Article en En | MEDLINE | ID: mdl-33682420
Nav1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 (1) and GDC-0310 (2), selective Nav1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Azetidinas / Benzamidas / Descubrimiento de Drogas / Canal de Sodio Activado por Voltaje NAV1.7 / Bloqueadores del Canal de Sodio Activado por Voltaje Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Azetidinas / Benzamidas / Descubrimiento de Drogas / Canal de Sodio Activado por Voltaje NAV1.7 / Bloqueadores del Canal de Sodio Activado por Voltaje Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos