QSAR and the Rational Design of Long-Acting Dual D_2-Receptor/β_2-Adrenoceptor Agonists

摘要

This paper describes the development of a QSAR model for the rational control of functional duration of topical long-acting dual D_2-receptor/β_-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. A QSAR model highlighted the importance of lipophilicity and ionization in controlling β_2 duration. It was found that design rules log D_(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 β_2 duration. Data presented strongly suggests that β_2 duration is primarily controlled by the membrane affinity of these compounds.