Your browser doesn't support javascript.
loading
Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2.
Liu, Chunjian; Lin, James; Langevine, Charles; Smith, Daniel; Li, Jianqing; Tokarski, John S; Khan, Javed; Ruzanov, Max; Strnad, Joann; Zupa-Fernandez, Adriana; Cheng, Lihong; Gillooly, Kathleen M; Shuster, David; Zhang, Yifan; Thankappan, Anil; McIntyre, Kim W; Chaudhry, Charu; Elzinga, Paul A; Chiney, Manoj; Chimalakonda, Anjaneya; Lombardo, Louis J; Macor, John E; Carter, Percy H; Burke, James R; Weinstein, David S.
Afiliación
  • Liu C; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Lin J; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Langevine C; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Smith D; Department of Discovery Synthesis, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Li J; Department of Discovery Synthesis, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Tokarski JS; Molecular Structure and Design, Molecular Discovery Technologies, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Khan J; Molecular Structure and Design, Molecular Discovery Technologies, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Ruzanov M; Molecular Structure and Design, Molecular Discovery Technologies, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Strnad J; Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Zupa-Fernandez A; Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Cheng L; Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Gillooly KM; Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Shuster D; Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Zhang Y; Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Thankappan A; Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • McIntyre KW; Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Chaudhry C; Leads Discovery and Optimization, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Elzinga PA; Metabolism and Pharmacokinetic Department, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Chiney M; Metabolism and Pharmacokinetic Department, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Chimalakonda A; Metabolism and Pharmacokinetic Department, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Lombardo LJ; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Macor JE; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Carter PH; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Burke JR; Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • Weinstein DS; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
J Med Chem ; 64(1): 677-694, 2021 01 14.
Article en En | MEDLINE | ID: mdl-33370104
ABSTRACT
A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxazoles / Ciclopropanos / Inhibidores de Proteínas Quinasas / TYK2 Quinasa / Descubrimiento de Drogas 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
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxazoles / Ciclopropanos / Inhibidores de Proteínas Quinasas / TYK2 Quinasa / Descubrimiento de Drogas 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