RESUMO
A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Álcoois/síntese química , Óxidos N-Cíclicos/síntese química , Inibidores de Fosfodiesterase/síntese química , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/metabolismo , Piridinas/síntese química , Álcoois/farmacocinética , Álcoois/farmacologia , Álcoois/toxicidade , Animais , Broncoconstrição/efeitos dos fármacos , Cristalografia por Raios X , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/farmacologia , Óxidos N-Cíclicos/toxicidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Cães , Canal de Potássio ERG1 , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go , Cobaias , Humanos , Técnicas In Vitro , Síndrome do QT Longo/induzido quimicamente , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/toxicidade , Ligação Proteica , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/toxicidade , Ratos , Saimiri , Ovinos , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Vômito/induzido quimicamenteRESUMO
In recognition of the tenth anniversary of the Safety Pharmacology Society (SPS), this review summarizes the significant events of the past 10years that have led to the birth, growth and evolution the SPS and presents a roadmap to the immediate-, intermediate- and long-term future of the SPS. The review discusses (i) the rationale for an optimal non-clinical Safety Pharmacology testing, (ii) the evolution of Safety Pharmacology over the last decade, (iii) its impact on drug discovery and development, (iv) the merits of adopting an integrated risk assessment approach, (v) the translation of non-clinical findings to humans and finally (vi) the future challenges and opportunities facing this discipline. Such challenges include the emergence of new molecular targets and new approaches to treat diseases, the rapid development of science and technologies, the growing regulatory concerns and associated number of guidance documents, and the need to train and educate the next generation of safety pharmacologist.