Application of quantitative structure-activity relationships in the development of the antiallergic pyranenamines.
QSAR techniques played a major role in development of the antiallergic pyranenamines (I). Graphical analysis of data resulting from an unsuccessful Topliss approach suggested that increased substituent hydrophilicity might enhance potency. The 3-NHAc-4-OH derivative which first resulted was an order of magnitude more potent than any preceding series member, and its deacylated congenar is clinical candidate SK&F 78729 (R1 = -NH2, R2 - OH, R3 = H). Further pursuit of hydrophilicity and other strategies suggested by multiple regression yielded 98 pyranenamines, the most active [R1 = R3 = NHCO(CHOH)2H, R2 = H] being 1000 times more potent than any original series member.
D002626:Chemistry, Pharmaceutical; D006860:Hydrogen Bonding; D006967:Hypersensitivity / Q000188:drug therapy*; D008954:Models, Biological; D011714:Pyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D011789:Quantum Theory; D012044:Regression Analysis; D012995:Solubility; D013329:Structure-Activity Relationship
D011714:Pyrans