RESUMO
A hit-to-lead optimization process was carried out on the high throughput screening hit compound 1 resulting in the identification of several potent and selective CCR1 receptor antagonists. Compound 37 shows the best overall profile with IC(50) values of <100 nM in binding and functional assays.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Receptores CCR1/antagonistas & inibidores , Cálcio/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Quimiocina CCL3/metabolismo , Quimiotaxia/efeitos dos fármacos , Humanos , Estrutura Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Piperidinas/síntese química , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRbeta agonist with an EC50 of 12 nM in the cofactor recruitment assay.
Assuntos
Proteínas de Ligação a DNA/agonistas , Indóis/química , Indóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Sítios de Ligação , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Receptores X do Fígado , Modelos Moleculares , Estrutura Molecular , Receptores Nucleares Órfãos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Relação Estrutura-Atividade , Regulação para CimaRESUMO
Synthesis and structure-activity relationship of a series of 4-(2-aryl-cyclopropylamino)-quinoline-3-carbonitrile derivatives as EGFR inhibitors is described. Compounds 29 and 30 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the functional cellular assay. They are moderately selective against other types of tyrosine kinases.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Nitrilas/química , Nitrilas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Inibidores Enzimáticos/síntese química , Nitrilas/síntese química , Quinolinas/síntese química , Relação Estrutura-AtividadeRESUMO
A structurally novel liver X receptor (LXR) agonist (1) was identified from internal compound collection utilizing the combination of structure-based virtual screening and high-throughput gene profiling. Compound 1 increased ABCA1 gene expression by eightfold and SREBP1c by threefold in differentiated THP-1 macrophage cell lines. Confirmation of its agonistic activity against LXR was obtained in the co-factor recruitment and reporter transactivation assays. Structure-activity relationship studies on compound 1 are described.
Assuntos
Proteínas de Ligação a DNA/agonistas , Regulação da Expressão Gênica/efeitos dos fármacos , Indóis/farmacologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/agonistas , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/fisiologia , Humanos , Indóis/síntese química , Receptores X do Fígado , Macrófagos/metabolismo , Modelos Químicos , Monócitos/citologia , Receptores Nucleares Órfãos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Relação Estrutura-AtividadeRESUMO
Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model.
Assuntos
Artrite Experimental/tratamento farmacológico , Compostos de Benzil/farmacologia , Ciclobutanos/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Administração Oral , Animais , Artrite Experimental/induzido quimicamente , Compostos de Benzil/química , Sítios de Ligação , Colágeno , Ciclobutanos/química , Modelos Animais de Doenças , Desenho de Fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Receptores CCR1 , Relação Estrutura-AtividadeRESUMO
alpha(4)beta(1) and alpha(4)beta(7) integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. The effectiveness of anti-integrin antibodies to attenuate a number of inflammatory/immune conditions provides a strong rationale to target integrins for drug development. Important advances have been made in identifying potent and selective candidates, peptides and peptidomimetics, for further development. Herein, we report the discovery of a series of novel N-benzoyl-L-biphenylalanine derivatives that are potent inhibitors of alpha4 integrins. The potency of the initial lead compound (1: IC(50) alpha(4)beta(7)/alpha(4)beta(1)=5/33 microM) was optimized via sequential manipulation of substituents to generate low nM, orally bioavailable dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. The SAR also led to the identification of several subnanomolar antagonists (134, 142, and 143). Compound 81 (TR-14035; IC(50) alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM) has completed Phase I studies in Europe. The synthesis, SAR and biological evaluation of these compounds are described.