RESUMO
We previously identified KCA-1490 [(-)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model.
Assuntos
Anti-Inflamatórios , Desenho de Fármacos , Inibidores da Fosfodiesterase 4 , Pirazóis/síntese química , Piridinas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Animais , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.
Assuntos
Anti-Inflamatórios/química , Broncodilatadores/química , Inibidores da Fosfodiesterase 3/química , Inibidores da Fosfodiesterase 4/química , Administração por Inalação , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Broncodilatadores/síntese química , Broncodilatadores/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Leucócitos/efeitos dos fármacos , Inibidores da Fosfodiesterase 3/síntese química , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/farmacologia , Ligação Proteica , Piridazinas/química , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. Here we show that a 4,4-dimethylpyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2H)-one ring of KCA-1490 whilst lacking a stereogenic centre. The 2- and 7-substituents in the pyrazolo[1,5-a]pyridine subunit markedly influence the PDE-inhibitory profile and can be adjusted to afford either potent PDE4-selective inhibitors or dual PDE3/4 inhibitors. A survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5-a]pyridine allowed further refinement of the inhibitory profile and identified 3-(8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)-4,4-dimethyl-1H-pyrazol-5(4H)-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Pirazolonas/química , Piridazinas/farmacologia , Piridinas/farmacologia , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/química , Piridazinas/síntese química , Piridazinas/química , Piridinas/síntese química , Piridinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An improved method for 4,4-dimethylpyrazolone synthesis with t-butylcarbazate was described. The applicability of this method to dihydropyridazinone formation was demonstrated. This method is useful for suppressing the side reaction caused by the high nucleophilicity of hydrazine.
Assuntos
Pirazolonas/síntese química , Piridazinas/síntese química , Técnicas de Química Analítica , Hidrazinas/química , Espectroscopia de Ressonância Magnética , Pirazolonas/química , Piridazinas/químicaRESUMO
(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.
Assuntos
Inibidores da Fosfodiesterase 3/química , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/síntese química , Broncodilatadores/química , Broncodilatadores/farmacologia , Desenho de Fármacos , Humanos , Modelos Moleculares , Inibidores da Fosfodiesterase 3/síntese química , Inibidores da Fosfodiesterase 4/síntese química , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Novel antibacterial biaryl oxazolidinones bearing an aza-, an oxa-, or a thiabicyclo[3.1.0]hex-6-yl ring system were synthesized, and their in vitro antibacterial activity and structure-activity relationships (SAR) were evaluated. Most of the synthesized biaryl bicyclo[3.1.0]hex-6-yl oxazolidinones showed good antibacterial activity against the Gram-positive and -negative bacteria tested. Regarding SAR trends among the C-ring subtypes, the pyridyl ring was preferable to the phenyl ring. The results showed that the structural variety of the C-ring has a greater impact on antibacterial activity than that of the B-ring. A cyano group at the D-ring C-6 position plays an important role in the highly potent antibacterial activity.
