RESUMO
Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.
Assuntos
Compostos de Bifenilo/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Piridazinas/farmacologia , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Piridazinas/síntese química , Piridazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times.
Assuntos
Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Sulfonas/química , Sulfonas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Cinética , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonas/síntese químicaRESUMO
Novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides have been identified as potent M3 muscarinic antagonists with a long duration of action in an in vivo model of bronchoconstriction. The synthesis, structure-activity relationships and biological evaluation of this series of compounds are reported.
Assuntos
Amidas/química , Antagonistas Muscarínicos/química , Compostos de Amônio Quaternário/química , Quinuclidinas/química , Receptor Muscarínico M3/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Sítios de Ligação , Broncoconstritores/síntese química , Broncoconstritores/química , Broncoconstritores/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacocinética , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Receptor Muscarínico M3/metabolismo , Relação Estrutura-AtividadeRESUMO
A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure-kinetic relationships (SKR) opened up the possibility of long receptor residence times.
Assuntos
Acetatos/química , Compostos Bicíclicos com Pontes/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Animais , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Microssomos Hepáticos/metabolismo , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.
Assuntos
Acetatos/química , Acetatos/farmacologia , Piperidinas/química , Pirazóis/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Administração Oral , Animais , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Meia-Vida , Humanos , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ≠ H) gives access to compounds with dissociation half-lives of ⩾ 24h.
Assuntos
Acetatos/química , Compostos Bicíclicos com Pontes/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Meia-Vida , Humanos , Ligação de Hidrogênio , Modelos Químicos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl benzyl substituents was found, from which compounds 27 and 63 were advanced to in vivo profiling.
Assuntos
Acetatos/química , Acetatos/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Humanos , Pirazóis/síntese química , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.
Assuntos
Acetatos/química , Pirazóis/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Animais , Meia-Vida , Ensaios de Triagem em Larga Escala , Ligação Proteica , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
Novel quaternary ammonium derivatives of N,N-disubstituted (3R)-quinuclidinyl carbamates have been identified as potent M(3) muscarinic antagonists with long duration of action in an in vivo model of bronchoconstriction. These compounds have also presented a high level of metabolic transformation (human liver microsomes). The synthesis, structure-activity relationships and biological evaluation of these compounds are reported.