RESUMO
A novel series of quinolinone-based adenosine A(2B) receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A(2B) antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM).
Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Quinolonas/química , Receptor A2B de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Técnicas de Química Combinatória , Avaliação Pré-Clínica de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Quinolonas/síntese química , Quinolonas/farmacologia , Receptor A2B de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1alpha (MIP-1alpha) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC(50) of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.
Assuntos
Pirrolidinas/síntese química , Receptores CCR1/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular , Quimiotaxia de Leucócito , Inibidores das Enzimas do Citocromo P-450 , Humanos , Técnicas In Vitro , Isoenzimas/antagonistas & inibidores , Microssomos Hepáticos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Pirrolidinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/farmacologiaRESUMO
A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.
Assuntos
Trifosfato de Adenosina/metabolismo , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Mitocôndrias/enzimologia , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Animais , Bovinos , Inibidores Enzimáticos/síntese química , Guanidinas/síntese química , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Relação Estrutura-AtividadeRESUMO
In this paper we show that 4-aryl-CH2-imidazole-substituted benzopyran compounds with 3S,4R-stereochemistry are cardioprotective by inhibiting the F1F0 mitochondrial ATP hydrolase. Compounds (e.g., 13) with 3R,4S-stereochemistry act as mitochondrial KATP openers. This resulted from an inversion of stereochemistry for the F1F0 mitochondrial ATP hydrolase vs mitochondrial KATP. Structure-activity relationships for the inhibition of mitochondrial ATP hydrolase are also delineated. It is not clear how 13 (3R,4S) can selectively inhibit the hydrolytic activity of the F1F0 mitochondrial enzyme without interfering with the synthase activity.