THE SQUALESTATINS - SYNTHESIS AND BIOLOGICAL-ACTIVITY OF SOME C3-MODIFIED ANALOGS - REPLACEMENT OF A CARBOXYLIC-ACID OR METHYL-ESTER WITH AN ISOELECTRONIC HETEROCYCLIC FUNCTIONALITY

A series of squalestatins modified at the C3-position with a heterocyc lic functionality was prepared and evaluated in, vitro as inhibitors o f squalene synthase (SQS). Structure-activity relationships for compou nds with the 4,6-dimethyloctenoate at C6(S1 analogues) were different from those for analogues lacking the C6 ester (H1 analogues), with a g reater dependence on the nature of the C3-substituent for the H1 serie s. Potent SQS inhibitory activity equivalent to that of H1 is retained by a C3-(tetrazol-5-yl) analogue, i.e., a carboxylic acid mimetic. Th e C3-methyl ester derivative is 10-fold less active than H1, and SQS i nhibitory activity similar to that of the methyl ester was retained on ly in those C3-heterocycle-substituted H1 analogues for which electros tatic potential maps of the C3-substituent were closely similar to tha t of a methyl ester.