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Novel phenylalanine derived diamides as Factor XIa inhibitors.
Smith, Leon M; Orwat, Michael J; Hu, Zilun; Han, Wei; Wang, Cailan; Rossi, Karen A; Gilligan, Paul J; Pabbisetty, Kumar B; Osuna, Honey; Corte, James R; Rendina, Alan R; Luettgen, Joseph M; Wong, Pancras C; Narayanan, Ranga; Harper, Timothy W; Bozarth, Jeffrey M; Crain, Earl J; Wei, Anzhi; Ramamurthy, Vidhyashankar; Morin, Paul E; Xin, Baomin; Zheng, Joanna; Seiffert, Dietmar A; Quan, Mimi L; Lam, Patrick Y S; Wexler, Ruth R; Pinto, Donald J P.
Affiliation
  • Smith LM; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States. Electronic address: leon.smith@bms.com.
  • Orwat MJ; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Hu Z; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Han W; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Wang C; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Rossi KA; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Gilligan PJ; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Pabbisetty KB; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Osuna H; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Corte JR; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Rendina AR; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Luettgen JM; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Wong PC; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Narayanan R; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Harper TW; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Bozarth JM; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Crain EJ; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Wei A; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Ramamurthy V; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Morin PE; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Xin B; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Zheng J; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Seiffert DA; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Quan ML; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Lam PYS; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Wexler RR; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
  • Pinto DJP; Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
Bioorg Med Chem Lett ; 26(2): 472-478, 2016 Jan 15.
Article in En | MEDLINE | ID: mdl-26704266
ABSTRACT
The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8µM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phenylalanine / Factor XIa / Anilides Type of study: Prognostic_studies Limits: Animals Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2016 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phenylalanine / Factor XIa / Anilides Type of study: Prognostic_studies Limits: Animals Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2016 Document type: Article