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Macrocyclic prolinyl acyl guanidines as inhibitors of ß-secretase (BACE).
Boy, Kenneth M; Guernon, Jason M; Wu, Yong-Jin; Zhang, Yunhui; Shi, Joe; Zhai, Weixu; Zhu, Shirong; Gerritz, Samuel W; Toyn, Jeremy H; Meredith, Jere E; Barten, Donna M; Burton, Catherine R; Albright, Charles F; Good, Andrew C; Grace, James E; Lentz, Kimberley A; Olson, Richard E; Macor, John E; Thompson, Lorin A.
Afiliação
  • Boy KM; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: boyk@bms.com.
  • Guernon JM; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Wu YJ; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Zhang Y; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Shi J; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Zhai W; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Zhu S; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Gerritz SW; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Toyn JH; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Meredith JE; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Barten DM; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Burton CR; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Albright CF; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Good AC; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Grace JE; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Lentz KA; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Olson RE; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Macor JE; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Thompson LA; Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett ; 25(22): 5040-7, 2015 Nov 15.
Article em En | MEDLINE | ID: mdl-26497283
ABSTRACT
The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Proteases / Prolina / Ácido Aspártico Endopeptidases / Compostos Macrocíclicos / Secretases da Proteína Precursora do Amiloide / Guanidinas Limite: Animals / Humans / Male Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2015 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Proteases / Prolina / Ácido Aspártico Endopeptidases / Compostos Macrocíclicos / Secretases da Proteína Precursora do Amiloide / Guanidinas Limite: Animals / Humans / Male Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2015 Tipo de documento: Article