SYMBIOTIC APPROACH TO DRUG DESIGN - ANTIHYPERTENSIVE BETA-ADRENERGIC BLOCKING-AGENTS

The symbiotic approach to drug design involves the incorporation of two mutually complementary biological activities into one entity by medicinal chemical hybridization. This approach has been applied to the design of the vasodilator/β-adrenoceptor antagonist 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (3). The vasodilating properties of this compound could be shown not to be due to β2-adrenergic agonism. As might be expected of a compound directed at two separate pharmacologic goals, the structure-activity relationships are very restrictive and minor structural variations markedly affect the overall biological results. For example, alterations in the aminohydroxypropoxy group, as in 13, which might have been expected to affect only β-adrenergic blockade, in fact were found to significantly influence the vasodilating properties. Thus, a bivalent drug such as 3 does not simply represent a combination of two separate activities into one molecule. Rather, the resulting biologic profile becomes an expression of the molecule as a whole. Regardless of the exact mechanism through which 3 may ultimately be found to exert its vasodilating effect, the application of the symbiotic approach to drug design has in this case led to compounds having the desired pharmacologic profile of two mutually supportive activities. Acute studies in man were terminated when 3 was found to be teratogenic in rabbits after chronic administration at high doses. In spite of the difficulties referred to above, we believe that this approach, in appropriate situations, represents a novel and useful strategy in drug design. © 1979, American Chemical Society. All rights reserved.