RESUMO
This paper describes the development of a QSAR model for the rational control of functional duration of topical long-acting dual D(2)-receptor/beta(2)-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. A QSAR model highlighted the importance of lipophilicity and ionization in controlling beta(2) duration. It was found that design rules logD(7.4) > 2, secondary amine pK(a) > 8.0, yielded ultra-long duration compounds. This model was used successfully to guide the design of long- and ultra-long-acting compounds. The QSAR model is discussed in terms of the exosite model, and the plasmalemma diffusion microkinetic hypothesis, for the control of beta(2) duration. Data presented strongly suggests that beta(2) duration is primarily controlled by the membrane affinity of these compounds.
Assuntos
Agonistas Adrenérgicos beta/química , Albuterol/análogos & derivados , Agonistas de Dopamina/química , Relação Quantitativa Estrutura-Atividade , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/farmacologia , Albuterol/farmacocinética , Algoritmos , Animais , Transporte Biológico , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/farmacologia , Desenho de Fármacos , Cobaias , Técnicas In Vitro , Cinética , Modelos Moleculares , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Xinafoato de Salmeterol , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Traqueia/fisiologiaRESUMO
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.