Jozwiak, K., Woo, A. Y. H., Tanga, M. J., Toll, L., Jimenez, L., Kozocas, J. A., … & Wainer, I. W. (2010). Comparative molecular field analysis of fenoterol derivatives: a platform towards highly selective and effective β2-adrenergic receptor agonists. Bioorganic & medicinal chemistry, 18(2), 728-736.
To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the β2-adrenergic receptor.
Out of 21 computationally designed structures 6 compounds were synthesized and characterized for β2-AR binding affinities, subtype selectivities and functional activities.
The best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with Kiβ2-AR = 0.28 μm, Kiβ1-AR/Kiβ2-AR = 573, EC50cAMP = 3.9 nm, EC50cardio = 16 nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure.
Keywords: Comparative molecular fields analysis, β2 selective agonist, Drug design