STRUCTURE-ACTIVITY RELATIONSHIP OF A SERIES OF PHENYLUREAS LINKED TO 4-PHENYLIMIDAZOLE - NOVEL POTENT INHIBITORS OF ACYL-COA CHOLESTEROL O-ACYLTRANSFERASE WITH ANTIATHEROSCLEROTIC ACTIVITY .2.

In our continuing search to find systemically bioavailable ACAT (acyl- CoA:cholesterol 0-acyl-transferase) inhibitors with more potent antiat herosclerotic effect than nyl-1H-imidazol-1-yl)propoxy]phenyl]-N'-pent ylurea (3), a series of phenylureas linked to 4-phenylimidazole were s ynthesized and evaluated for in vitro inhibitory activity toward both aortic and intestinal ACATs, and for in vivo hypocholesterolemic activ ity. The structure-activity relationships (SARs) were studied by strat egic modification of five regions in the molecule of 3, i.e., by intro ducing functional groups or exchanging carbon atoms for heteroatoms. T he SAR studies allowed us to select optimum substituents in the five r egions, as follows. (1) Dimethylamino was convertible into nitro, meth yl, ethyl, propyl, isopropyl, and chloro. On the basis of preliminary pharmacokinetic studies, the methyl group in the ortho-position of the phenylurea was selected. (2) Butyl, pentyl, isopentyl, and neopentyl were better substituents in the urea moiety. (3) Propoxy was the optim al moiety in the bridging portion. (4) Proton, methyl, ethyl, isopropy l, hydroxymethyl, and chloro were better substituents at the 5-positio n of the imidazole moiety. (5) An unsubstituted phenyl ring was select ed as the phenyl group of phenylimidazole. The subsequent comparison s tudies of compounds containing various combinations of the optimum sub stituents in each region resulted in the selection of two compounds (6 7, 68) for further pharmacological and toxicological testing. These co mpounds were orally bioavailable, and possessed potent in vitro aortic ACAT inhibitory activity (IC50 = 0.16 and 0.012 muM, respectively) an d in vivo cholesterol lowering effect (46 % and 52 % at 1 mg/ kg po, r espectively). In particular, 68 was 10-fold more potent in the in vitr o aortic ACAT assay and 5-fold more potent with respect to hypoholeste rolemic activity in vivo than 3.