RESUMO
Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.
Assuntos
Compostos de Bifenilo/farmacocinética , Ácidos Hidroxâmicos/farmacocinética , Inibidores de Metaloproteinases de Matriz , Administração Oral , Animais , Antineoplásicos/sangue , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Compostos de Bifenilo/sangue , Compostos de Bifenilo/síntese química , Divisão Celular/efeitos dos fármacos , Cães , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Haplorrinos , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/síntese química , Concentração Inibidora 50 , Injeções Intravenosas , Taxa de Depuração Metabólica , Neoplasias Experimentais/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Two series of compounds synthesized as specific matrix metalloproteinase (MMP) inhibitors have been evaluated for their inhibition of non-MMPs. In a series of substituted succinyl hydroxamic acids, some were found to be significant (IC50 < 1 microM) inhibitors of leucine (microsomal) aminopeptidase, neprilysin (3.4.24.11), and thermolysin. Macrocyclic compounds in which the alpha carbon of the succinyl hydroxamate is linked to the side chain of the P2' amino acid were found to be good inhibitors of aminopeptidase, but not of neprilysin or thermolysin. Compounds of neither series were found to be significant inhibitors of angiotensin converting enzyme or carboxypeptidase A.
Assuntos
Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina , Animais , Proteínas de Bactérias , Carboxipeptidases/antagonistas & inibidores , Carboxipeptidases A , Bovinos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/metabolismo , Concentração Inibidora 50 , Leucil Aminopeptidase/antagonistas & inibidores , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Coelhos , Ratos , Suínos , Termolisina/antagonistas & inibidores , Zinco/metabolismoRESUMO
Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.
Assuntos
Imidazóis/síntese química , Fator de Ativação de Plaquetas/antagonistas & inibidores , Inibidores da Agregação Plaquetária/síntese química , Glicoproteínas da Membrana de Plaquetas/metabolismo , Piridinas/síntese química , Receptores de Superfície Celular , Receptores Acoplados a Proteínas G , Animais , Disponibilidade Biológica , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Permeabilidade Capilar/efeitos dos fármacos , Cães , Feminino , Cobaias , Humanos , Imidazóis/química , Imidazóis/farmacologia , Macaca fascicularis , Masculino , Estrutura Molecular , Fator de Ativação de Plaquetas/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.
Assuntos
Colagenases/química , Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Fenilalanina/análogos & derivados , Inibidores de Proteases/síntese química , Tiofenos/química , Tiofenos/síntese química , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Indicadores e Reagentes , Cinética , Metaloproteinase 8 da Matriz , Modelos Moleculares , Fenilalanina/química , Fenilalanina/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Succinatos/síntese química , Succinatos/química , Succinatos/farmacologia , Tiofenos/farmacologiaRESUMO
(2RS,4R)-3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles represent a new class of potent, orally active antagonists of platelet activating factor (PAF). The compounds were prepared by acylation of the magnesium or zinc salts of substituted indoles with (2RS,4R)-2-(3-pyridinyl)-3-(tert-butoxycarbonyl)thiazolidin-4-oyl chloride. The 3-acylindole moiety functions as a hydrolytically stabilized and conformationally restricted anilide replacement, which imparts a considerable boost in potency to the series. Structure-activity relationships observed for substitution on the indole ring system are discussed. Members of the series compare favorably with other reported PAF antagonists.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Edema/tratamento farmacológico , Indóis/farmacologia , Fator de Ativação de Plaquetas/antagonistas & inibidores , Tiazóis/farmacologia , Administração Oral , Animais , Edema/induzido quimicamente , Técnicas In Vitro , Indóis/síntese química , Indóis/química , Indóis/uso terapêutico , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Coelhos , Ratos , Ratos Sprague-Dawley , Serotonina/sangue , Pele/efeitos dos fármacos , Pele/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/uso terapêuticoRESUMO
In the male retired breeder rat, arachidonic acid 1a and 2,2-dimethylarachidonic acid 3a exhibited plasma platelet disaggregation as measured after 3 hr after the compounds were administered intragastrically at 15 and 13 mg/kg/rat mean effective dose (MED), respectively. The corresponding p-t-butylphenol ester of the acids showed a remarkable potentiation of platelet disaggregation. The MED for p-t-butylphenol ester of AA was 1.1 mg/kg/rat.