RESUMO
Following the discovery of RPR200765, a series of pyrimidine analogues have been prepared as backups. Amongst them, RPR203494 was identified with a better in vitro profile than RPR200765A.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Pirimidinas/farmacologia , Análise de Variância , Animais , Área Sob a Curva , Artrite Reumatoide/tratamento farmacológico , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Pirimidinas/química , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Proteínas Recombinantes/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
The fifth paper in this series describes the culmination of our investigations into the development of a potent and selective ET(A) receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of several ET(A) antagonists prepared previously identified a common cationic binding site which prompted synthesis of phenoxyphenylacetic acid derivative 13a, which showed good in vitro activity (IC(50) 59 nM, rat aortic ET(A)). Optimization of 13a led to the identification of 27b, which exhibited an IC(50) of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far better pharmacokinetic profile and in vivo potency (75 micromol/kg) and was duly proposed and accepted as a development candidate.
Assuntos
Antagonistas dos Receptores de Endotelina , Fenilacetatos/síntese química , Piridinas/síntese química , Administração Oral , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Ligação Competitiva , Disponibilidade Biológica , Linhagem Celular , Cerebelo/metabolismo , Estado de Descerebração , Endotelina-1/metabolismo , Técnicas In Vitro , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiologia , Fenilacetatos/química , Fenilacetatos/metabolismo , Fenilacetatos/farmacologia , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Receptor de Endotelina A , Receptores de Endotelina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)b utanoi c acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.
Assuntos
Antagonistas dos Receptores de Endotelina , Fenilbutiratos/síntese química , Piridinas/síntese química , Administração Oral , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Linhagem Celular , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Estado de Descerebração , Injeções Intravenosas , Masculino , Modelos Moleculares , Conformação Molecular , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Fenilbutiratos/química , Fenilbutiratos/farmacocinética , Fenilbutiratos/farmacologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A , Receptor de Endotelina B , Relação Estrutura-Atividade , Vasoconstrição/efeitos dos fármacosRESUMO
This publication describes the synthesis and optimization of a novel series of stilbene endothelin antagonists. Analysis of the SAR established for previous papers in this series prompted the design and synthesis of (Z)-4-phenyl-5-(3-benzyloxyphenyl)pent-4-enoic acid 3 which was found to be a moderately active inhibitor of the binding of [125I]ET-1 to ETA receptors with an IC50 of 6 microM. More interestingly, the intermediate compound (E)-2-phenyl-3-(3-benzyloxyphenyl)propenoic acid 5 was equiactive with 3. Optimization of 5 resulted in the preparation of (E)-2-phenyl-3-(2-cyano-5-(thien-3-ylmethoxy))phenylprope noic acid 18 (RPR111723) which had an IC50 in the binding assay of 80 nM on the ETA receptor and a pKB of 6.5 in the functional assay, measured on rat aortic strips. Reduction of the acid group of 5 gave the first nonacidic ETA antagonist in our series, (E)-2-phenyl-3-(3-benzyloxyphenoxy)prop2-enol 6 with an IC50 of 20 microM. Optimization of 6 resulted in the preparation of 2-(2-methylphenyl)-3-(2-cyano-5-(thien-3-ylmethyl)phenyl)pro p-2-enol 33 with an IC50 of 300 nM on the ETA receptor.
Assuntos
Antagonistas dos Receptores de Endotelina , Fenilpropionatos/síntese química , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/fisiologia , Linhagem Celular , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Técnicas In Vitro , Masculino , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A , Relação Estrutura-AtividadeRESUMO
A series of phenothiazines demonstrating inhibition of RANTES binding to THP-1 cell membranes has been identified. The lead compound RP23618 (IC50 = 3 microM) was found to inhibit specific binding of 125I-RANTES, but not 125I-MCP-1 to THP-1 cell membranes and furthermore to antagonize RANTES, but not MCP-1-induced chemotaxis of THP-1 cells.
Assuntos
Quimiocina CCL5/antagonistas & inibidores , Fenotiazinas/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Quimiocina CCL2/metabolismo , Desenho de Fármacos , Humanos , Indicadores e Reagentes , Radioisótopos do Iodo , Cinética , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The generation of new chemical leads for biological targets is a very challenging task for researchers in the pharmaceutical industry. The design of representative screening sets and combinatorial libraries is central to achieving this objective. In this paper, we describe a novel molecular descriptor, the Diverse Property-Derived (DPD) code, that contains information about key molecular and physicochemical properties of a molecule. The utility of this descriptor is explored through its application for the selection of a maximally diverse representative screening set, through the selection of secondary screening sets to obtain more information concerning the structure-activity relationships (SAR) of a particular target receptor, and through the profiling of combinatorial libraries. The usefulness of physicochemical/molecular property descriptors, such as the DPD code, is discussed critically.
Assuntos
Bases de Dados Factuais , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Fenômenos Químicos , Físico-Química , Estudos de Avaliação como Assunto , Software , Design de Software , Relação Estrutura-AtividadeRESUMO
The synthesis and biological activity of trans-(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamid+ ++ e 1-oxide (8a, RP 49356) and analogues is reported. These compounds constitute a new structural class of K(+)-channel opener. The effects of changes in pyridyl group, thioamide, and thiane ring on in vitro K(+)-channel opening reactivity are discussed. A 3-pyridyl or 3-quinolyl group, a small N-alkyl thioamide function, and a thiane oxide ring, in which the sulfoxide is in a trans relationship to the thioamide, are preferred for activity. Selected compounds were tested intravenously in the normotensive anaesthetized rat for hypotensive effects, and the activities reflect their in vitro K(+)-channel opening activity. This led to further evaluation of compound 8a and the selection of the (-)-enantiomer 8b (RP 52891) for development as an antihypertensive and antianginal agent.