INHIBITORS OF ACYL-COA-CHOLESTEROL ACYLTRANSFERASE (ACAT) .7. DEVELOPMENT OF A SERIES OF SUBSTITUTED N-PHENYL-N'-[(1-PHENYLCYCLOPENTYL)METHYL]UREAS WITH ENHANCED HYPOCHOLESTEROLEMIC ACTIVITY

We recently described our initial structure-activity relationship (SAR ) studies on a series of N-phenyl-N'-aralkyl- and N-phenyl-N'-(1-pheny lcycloalkyl)ureas as inhibitors of acyl-CoA: cholesterol acyltransfera se (ACAT). From this series of analogs, compound 1 (PD 129337) was ide ntified as a potent inhibitor of ACAT with art IC50 value of 17 nM. It was also shown to dose-dependently lower plasma cholesterol in choles terol-fed rats. However, further investigation led to the suggestion t hat this compound was poorly absorbed, due to a lack of efficacy when administered by gavage in an aqueous vehicle. To overcome this deficie ncy, we continued our SAR study on this novel series of ACAT inhibitor s using an acute in vivo screen in which the compounds are administere d to rats in an aqueous, CMC/Tween suspension vehicle. Modification of the N-phenyl moiety by incorporating functional groups which were ame nable to forming salts and/or polar groups to reduce lipophilicity led to the identification of several inhibitors which displayed excellent efficacy employing this protocol. Overall, substitution on the phenyl ring in the ortho, meta, or para positions led to inhibitors with onl y a slight decrease in potency in vitro compared to the parent unsubst ituted compound. Bulkier groups in the para position tended to lower t he ACAT inhibitory activity in vitro. Polar groups, such as carboxyl ( 33, 34), lowered in vitro activity significantly, suggesting that pola r-ionic interactions are disfavored for the enzyme activity. From this series, compound 28 was evaluated further in secondary in vivo screen s. In a chronic cholesterol-fed rat model of hypercholesterolemia, com pound 28 dose-dependently reduced nonHDL cholesterol and significantly elevated HDL cholesterol. It showed significantly greater aqueous sol ubility than the parent compound 1. However, it was shown to cause adr enal toxicity in guinea pigs. This led us to design a series of homolo gs (44-51) with increased basicity and lower lipophilicity. Some of th ese compounds were more potent ACAT inhibitors in vitro and demonstrat ed excellent hypocholesterolemic activity in vivo. Interestingly, comp ound 45, unlike 28, did not produce adrenal toxicity in guinea pigs an d demonstrated excellent lipid-modulating activity in the chronic mode l of preestablished dyslipidemia in rats.