RESUMO
Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.
Assuntos
Acridinas/síntese química , IMP Desidrogenase/antagonistas & inibidores , Piperazinas/síntese química , Acridinas/farmacologia , Acridinas/toxicidade , Administração Oral , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Linhagem Celular , Proliferação de Células , Trato Gastrointestinal/efeitos dos fármacos , Meia-Vida , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Macaca fascicularis , Masculino , Piperazinas/farmacologia , Piperazinas/toxicidade , Ratos , Ratos Endogâmicos Lew , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.
Assuntos
Anti-Inflamatórios/química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Quinoxalinas/química , Quinoxalinas/farmacocinética , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Disponibilidade Biológica , Citocinas/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Ligação de Hidrogênio , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pirazinas/química , Pirazinas/farmacologia , Quinoxalinas/farmacologia , Quinases da Família src/antagonistas & inibidoresRESUMO
Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats.
Assuntos
Inibidores Enzimáticos/síntese química , IMP Desidrogenase/antagonistas & inibidores , Morfolinas/síntese química , Ácido Micofenólico/análogos & derivados , Oxazóis/síntese química , Animais , Formação de Anticorpos/efeitos dos fármacos , Artrite Experimental/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Morfolinas/química , Morfolinas/farmacologia , Ácido Micofenólico/farmacologia , Oxazóis/química , Oxazóis/farmacologia , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-AtividadeRESUMO
[structure: see text] A modified approach to the synthesis of 2-(N-aryl)-1,3-oxazoles, employing an optimized iminophosphorane/heterocumulene-mediated methodology, and its application to the synthesis of BMS-337197, a potent inhibitor of IMPDH, are described.
Assuntos
Inibidores Enzimáticos/síntese química , IMP Desidrogenase/antagonistas & inibidores , Oxazóis/síntese química , Oxazóis/químicaRESUMO
A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.
Assuntos
Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Indóis/farmacologia , Catálise , Cinética , Relação Estrutura-AtividadeRESUMO
A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Antivirais/síntese química , Antivirais/farmacologia , Antivirais/toxicidade , Cristalografia por Raios X , Inibidores Enzimáticos/toxicidade , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/patologia , Imunossupressores/síntese química , Imunossupressores/farmacologia , Imunossupressores/toxicidade , Indicadores e Reagentes , Relação Estrutura-AtividadeRESUMO
A series of novel guanidine-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Guanidina/análogos & derivados , Guanidina/síntese química , IMP Desidrogenase/antagonistas & inibidores , Antivirais/síntese química , Antivirais/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Guanidina/farmacologia , Humanos , Indicadores e Reagentes , Relação Estrutura-AtividadeRESUMO
A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase is described. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are presented.
Assuntos
Diamida/química , Diamida/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Catálise , Relação Estrutura-AtividadeRESUMO
A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.
Assuntos
IMP Desidrogenase/antagonistas & inibidores , Triazinas/síntese química , Triazinas/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Triazinas/químicaRESUMO
A series of anilino(imidazoquinoxaline) analogues bearing solubilizing side chains at the 6- and 7-positions of the fused phenyl ring has been prepared and evaluated for inhibition against Lck enzyme and of T-cell proliferation. Significant improvement of the cellular activity was achieved over the initial lead, compound 2.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Divisão Celular/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacosRESUMO
A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Quinolonas/síntese química , Quinolonas/farmacologia , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Fenômenos Químicos , Físico-Química , Cristalografia por Raios X , Humanos , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologiaRESUMO
The synthesis and the structure-activity relationships (SAR) of analogues derived from the introduction of basic residues on ring D of quinolone-based inhibitors of IMPDH are described. This led to the identification of compound 27 as a potent inhibitor of IMPDH with significantly improved aqueous solubility over the lead compound 1.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Quinolonas/síntese química , Quinolonas/farmacologia , Humanos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.
Assuntos
Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Quinoxalinas/síntese química , Quinases da Família src/antagonistas & inibidores , Animais , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Cinética , Ativação Linfocitária/efeitos dos fármacos , Modelos Moleculares , Conformação Molecular , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Linfócitos T/imunologiaRESUMO
The first reported structure-activity relationships (SARs) about the N-[3-methoxy-4-(5-oxazolyl)phenyl moiety for a series of recently disclosed inosine monophosphate dehydrogenase (IMPDH) inhibitors are described. The syntheses and in vitro inhibitory values for IMPDH II, and T-cell proliferation (for select analogues) are given.