Structure-activity relationship studies of phenoxypropanolamine derivatives for beta 3-adrenergic activity

In this study, some compounds of phenoxypropanolamine (SWR-0342SA) derivatives were found to possess beta 3-adrenoceptor (beta 3-AR) agonistic activity. Addition and deletion of the substituents on phenoxyacetate, chain length variation between two aromatic rings, conversion of phenoxypropanolamine to phenylethanolamine, insertion of double bonds and another ether group in the side chain between two phenyl rings in SWR-0342SA derivatives resulted in novel phenoxypropanolamine and phenylethanolamine compounds. This study was performed to evaluate the structural modification of the parent SWR-0342SA and their effects on the binding affinities as well as functional activities of these derivatives using COS-7 cells and CHO cells expressing human beta 1, beta 2, beta 3-AR and only beta 3-AR respectively. Compounds SWR-0342SA, SWR-0339SA (S-enantiomer with trans-ethylidene group), SWR-0315NA (non-isomeric with racemic ethylidene group and sodium salt), and SWR-0334NA (non-isomeric with trans-ethylidene group and sodium salt), all belonging to phenoxypropanolamine group, were found to have high binding and functional activities and were supposed to be potent beta 3-AR agonists. Since many of the phenoxypropanolamine compounds acts as antagonists to beta 1- and beta 2-ARs, these derivatives have also been evaluated for their affinity to beta 1- and beta 2-ARs. The pKi values of these derivatives to beta-AR subtypes were also compared. These compounds show little selectivities towards beta 3-AR subtypes.