RESUMO
The hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system prompted us to design and synthesize a hydrophilic piperidine analog to improve the side effect profile of Ariflo 1, which is an orally active second-generation PDE4 inhibitor. During evaluation of various water-soluble piperidine analogs, 2a-b, 11b-14b, and 17a showed therapeutic potential in cross-species comparison studies. The following three findings were obtained: (1) The hydroxamic acid group, a well known metal chelator, caused a marked increase of inhibitory activity. (2) Water-soluble piperidine analogs lacked the configurational isomerism of Ariflo 1 without loss of inhibitory activity. (3) Replacement of the 4-methoxy residue with a difluoromethoxy residue led to an increase of in vivo potency. Structure-activity relationships are presented. Single-dose rat pharmacokinetic data for 11b, 12b, and 17a are also presented.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Inibidores de Fosfodiesterase/síntese química , Piridinas/síntese química , Acetatos/química , Administração Oral , Animais , Quelantes/síntese química , Quelantes/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Ácidos Cicloexanocarboxílicos/química , Humanos , Ácidos Hidroxâmicos/química , Isomerismo , Nitrilas , Inibidores de Fosfodiesterase/farmacologia , Piridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and biological evaluation of new phosphodiesterase type 4 inhibitors, which possess new templates instead of a cyclohexane ring, are described. The mode of interaction with the enzyme is discussed based on the structure-activity relationship (SAR) data obtained for the synthesized inhibitors. Furthermore, the roles of three pharmacophores, a catechol moiety, a nitrile moiety, and acidic moieties, are discussed using in silico docking studies. More detailed biological evaluations of selected compounds are also presented.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Animais , Sítios de Ligação , Broncoconstrição/efeitos dos fármacos , Simulação por Computador , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Furões , Esvaziamento Gástrico/efeitos dos fármacos , Cobaias , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Rolipram/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Vômito/tratamento farmacológicoRESUMO
A series of 4-anilinopyrazolopyridine derivatives were synthesized and biologically evaluated as inhibitors of phosphodiesterase (PDE4). Chemical modification of 3, a structurally new chemical lead that was found in our in-house library, was focused on 1- and 3-substituents. Full details of the discovery of a new orally active chemical lead 5 are presented. Structure-activity relationship data, pharmacological evaluation, and the subtype selectivity study are also presented.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Pirazóis/síntese química , Piridinas/síntese química , Animais , Broncoconstrição/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Furões , Esvaziamento Gástrico/efeitos dos fármacos , Cobaias , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Masculino , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , SRS-A/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Vômito/induzido quimicamenteRESUMO
The design, synthesis, and biological evaluation of a series of pyrazolopyridines was carried out. Structural optimization of the aniline moiety of 4-anilinopyrazolopyridine derivative 3a, which is one of the newly discovered chemical leads for PDE4 inhibitors from our in-house library, was performed successfully. The details of the discovery of new orally active PDE4 inhibitors, which are expected to show therapeutic potential, are presented and their structure-activity relationships are discussed. Pharmacological evaluation and pharmacokinetic data for representative compounds are also presented.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Compostos de Anilina/química , Animais , Bioensaio , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Desenho de Fármacos , Furões , Cobaias , Humanos , Masculino , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Pirazóis/síntese química , Piridinas/síntese química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Células U937RESUMO
Based on the promising results obtained by the clinical trial of Ariflo, further optimization of the spatial arrangement of the three pharmacophores (the carboxylic acid moiety, nitrile moiety and 3-cyclopentyloxy-4-methoxyphenyl moiety) in the structure of Ariflo 1 was attempted using a bicyclo[3 ?3 ?0]octane template with more stereochemical diversity than the cyclohexane template of Ariflo 1. Biological evaluation of the decyanated analogs and further optimization of the cyclopentyloxy moiety of 2a-b were also performed. Among the compounds tested, 2a, 7a-b and 12a were found to be orally active and were estimated to have therapeutic potential based on cross-species and same-species comparisons. The structure-activity relationships (SARs) of these compounds were investigated and pharmacokinetic data for 2a and 7b were also obtained by single-dose studies in rats.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/uso terapêutico , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Administração Oral , Animais , Broncoconstrição/efeitos dos fármacos , Broncoconstrição/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Furões , Esvaziamento Gástrico/efeitos dos fármacos , Cobaias , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Inibidores de Fosfodiesterase/farmacocinética , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo , Células U937RESUMO
Based on the successful results in the clinical trial of Ariflo, further optimization of the spatial arrangement of the three pharmacophores (carboxylic acid moiety, nitrile moiety and 3-cyclopentyl-4-methoxyphenyl moiety) in the structure of Ariflo 1 was attempted using a bicyclo[3.3.0]octane template instead of a cyclohexane template. As a result, 2a, 7a and 7b were found to be orally active and were predicted to have an improved therapeutic potential based on evaluation by cross-species and same-species comparisons. Structure-activity relationships (SARs) of these compounds are also discussed.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/uso terapêutico , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Administração Oral , Animais , Broncoconstrição/efeitos dos fármacos , Broncoconstrição/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Humanos , Inibidores de Fosfodiesterase/administração & dosagem , Ratos , Células U937RESUMO
Structural optimization of pyrazolopyridine derivative 2, which is one of the newly discovered chemical leads for PDE4 inhibitors from our in-house library, was carried out successfully. The process of discovery of new orally active PDE4 inhibitors, which are expected to possess therapeutic potential, is presented and their structure-activity relationships are discussed.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/uso terapêutico , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Administração Oral , Animais , Broncoconstrição/efeitos dos fármacos , Broncoconstrição/fisiologia , Broncoconstritores/administração & dosagem , Broncoconstritores/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Furões , Esvaziamento Gástrico/efeitos dos fármacos , Cobaias , Humanos , Inibidores de Fosfodiesterase/química , Pirazóis/administração & dosagem , Pirazóis/química , Pirazóis/uso terapêutico , Piridinas/administração & dosagem , Piridinas/química , Piridinas/uso terapêutico , Ratos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Vômito/induzido quimicamenteRESUMO
Based on the hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system (CNS), design and synthesis of a hydrophilic analogue is considered to be one approach to improving the side-effect profile of Ariflo 1. Water-soluble piperidine derivatives were found to possess therapeutic potential.