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Chem Biol Drug Des ; 78(5): 739-48, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21883956


Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton's tyrosine kinase and IL-2-inducible T-cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X-ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 Å resolution and PP2 at 1.9 Å resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well-ordered protein conformation that includes an open/extended activation loop and a stabilized DFG-motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG-motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.

Cromossomos Humanos X , Proteínas Tirosina Quinases/química , Tirosina Quinase da Agamaglobulinemia , Sítios de Ligação , Cristalografia por Raios X , Dasatinibe , Humanos , Ligação Proteica , Inibidores de Proteínas Quinases/química , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/química , Tiazóis/química , Quinases da Família src/química , Quinases da Família src/metabolismo
J Med Chem ; 53(9): 3814-30, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20405922


Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.

Hidantoínas/farmacocinética , Fatores Imunológicos/química , Antígeno-1 Associado à Função Linfocitária/efeitos dos fármacos , Ácidos Nicotínicos/farmacocinética , Humanos , Hidantoínas/farmacologia , Antígeno-1 Associado à Função Linfocitária/química , Antígeno-1 Associado à Função Linfocitária/imunologia , Ácidos Nicotínicos/toxicidade , Relação Estrutura-Atividade
Bioorg Med Chem Lett ; 12(1): 45-9, 2002 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-11738570


A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

Dipeptídeos/farmacocinética , Fibrinolíticos/farmacocinética , Sulfonamidas/farmacocinética , Trombina/antagonistas & inibidores , Administração Oral , Animais , Sítios de Ligação , Cristalografia por Raios X , Dipeptídeos/administração & dosagem , Dipeptídeos/química , Modelos Animais de Doenças , Cães , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/administração & dosagem , Fibrinolíticos/química , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Camundongos , Inibidores de Serino Proteinase/administração & dosagem , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/química , Trombose/tratamento farmacológico , Trombose/prevenção & controle