RESUMO
We have investigated the SAR of a series of pyrimidinone-containing Cdc7 kinase inhibitors. A wide range of amine substitutions give potent compounds with activities (K(i)) less than 1nM. Kinase selectivity is reasonable and cytotoxicity corresponds to inhibition of MCM2 phosphorylation.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacologia , Aminas/química , Aminas/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Humanos , Componente 2 do Complexo de Manutenção de Minicromossomo , Proteínas Nucleares/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
Based on screening hit 1, a series of tricyclic quinoxalinones have been designed and evaluated for inhibition of PARP-1. Substitutions at the 7- and 8-positions of the quinoxalinone ring led to a number of compounds with good enzymatic and cellular potency. The tricyclic quinoxalinone class is sensitive to modifications of both the amine substituent and the tricyclic core. The synthesis and structure-activity relationship studies are presented.
Assuntos
Química Farmacêutica/métodos , Inibidores de Poli(ADP-Ribose) Polimerases , Quinoxalinas/química , Quinoxalinas/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Núcleo Celular/metabolismo , Reparo do DNA , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cinética , Modelos Moleculares , Conformação Molecular , Niacinamida/química , Relação Estrutura-AtividadeRESUMO
A peptidomimetic inhibitor of the integrin alpha(v)beta(3) has been substantially modified to produce several new nonpeptidic antagonists. These inhibitors are simpler to synthesize and belong to new classes of scaffolds. Some of the compounds served as the initial lead for further optimization, which led to the discovery of potent and selective inhibitors of the integrin alpha(v)beta(3).
Assuntos
Acetatos/síntese química , Integrina alfaVbeta3/antagonistas & inibidores , Propionatos/síntese química , Estilbenos/síntese química , Acetatos/química , Animais , Humanos , Integrina alfaVbeta3/química , Propionatos/química , Estilbenos/químicaRESUMO
The synthesis and biological evaluation of a series of heterocyclic analogues of the previously reported LTA(4) hydrolase inhibitor 1b are described. Imidazopyridine and purine analogues are specifically highlighted with several demonstrating excellent potency in our in vitro assays, as well as good oral activity in a mouse ex vivo assay.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Purinas/síntese química , Purinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Epóxido Hidrolases/sangue , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Camundongos , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The synthesis and biological evaluation of a series of functionalized pyrrolidine- and piperidine-containing analogues of our lead LTA(4) hydrolase inhibitor, SC-57461A, is described. A number of compounds showed excellent potency in our in vitro screens and several demonstrated good oral activity in a mouse ex vivo assay. These efforts led to the identification of SC-56938 (14) as a potent, orally active inhibitor of LTA(4) hydrolase.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Piperidinas/química , Piperidinas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , beta-Alanina/análogos & derivados , beta-Alanina/química , Administração Oral , Animais , Humanos , Concentração Inibidora 50 , Camundongos , Relação Estrutura-AtividadeRESUMO
Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention in these disease states, since the action of this enzyme is the rate-limiting step in the production of LTB(4). Our previous efforts focused on the exploration of a series of analogues related to screening hit SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) and resulted in the identification of potent, orally active inhibitors such as 2. Additional structure-activity relationship studies around this structural class resulted in the identification of a series of alpha-, beta-, and gamma-amino acid analogues that are potent inhibitors of the LTA(4) hydrolase enzyme and demonstrated good oral activity in a mouse ex vivo whole blood LTB(4) production assay. The efforts leading to the identification of clinical candidate SC-57461A (8d, 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described.