ABSTRACT
Structure-activity relationships (SARs) are derived by considering the phannacological response to the administration of an analogous series of compounds. Thus the effects of systematic structural changes are quantified and compared, and optimal activity correlated with a specific set of structural characteristics in the molecule. These may take the form of such parameters as the nature and location of specific chemical groups and stereochemical features. As the published activity data on the differing series of A TP-sensitive potassium channel activators (KCAs), or openers, has increased, so have SARs continued to accumulate for the benzopyran, or chroman, based KCAs derived from the pioneer compound cromakalim (CRK), 1. The topic has been reviewed specifically (McCaully, 1991), and formed the major part of a chapter devoted to the SARs of all KCA structural types (Evans eta/., 1992). In this review of benzopyran KCA SARs the earlier work will be included, but emphasis will be placed on more recent findings. As has been stated previously (Evans eta/., 1992), exact comparisons between analogues described in different studies are not easily made, particularly because of the diversity of indications for which the KCAs are claimed. Nevertheless, compounds can be ranked for potency, because in most studies comparisons have been made with CRK or its biologically active 3S,4R enantiomer levcromakalim (LCRK) 2, or the other lead compounds described later. In the majority of studies compounds have been compared for their in vivo effects on rat vascular smooth muscle, or guinea-pig tracheal smooth muscle, or for in vivo effects following oral administration to the spontaneously hypertensive rat (SHR). In addition there have been more recent reports on studies of KCA induced relaxation of rat detrusor muscle. This confirms that there are studies in progress aimed at the generation of KCA molecules that have selective effects on smooth muscle types other than those of the vasculature and airways. It is clear that highly desirable targets for medicinal chemistry are KCAs with appropriate selectivity for the different disease states involving smooth muscle and K channel dysfunction, and the study of SARs is one facet in this process.
