RP 73163, a novel systemic ACAT-Inhibitor induces coarse vacuolation and impairs steroid hormone metabolism in guinea pig adrenocortical cells

α-Substituted Malonester Amides: Tools To Define the Relationship between ACAT Inhibition and Adrenal Toxicity

“…The authors speculated that this inhibition of cholesterol 17R-reductase activity may be the source of the coarse vacuolation produced by RP 73163, although ACAT inhibition could not be ruled out. 16 It was recently disclosed that FR 145237, a potent ACAT inhibitor possessing direct antiatherosclerotic activity at the artery wall, 17 also produced adrenal toxicity in normal rabbits after a single iv dose. 18 Surprisingly, FR 145237 did not induce adrenal toxicity in low-density lipoprotein receptor deficient WHHL rabbits, despite producing adrenal drug concentrations equivalent to those found in the normal rabbits.…”

Inhibitors of Acyl-CoA:Cholesterol O-Acyltransferase. 3. Discovery of a Novel Series of N-Alkyl-N-[(fluorophenoxy)benzyl]-N‘-arylureas with Weak Toxicological Effects on Adrenal Glands

“…Despite numerous studies on potent ACAT inhibitors, in clinical trials poor efficacy has been found, and up to the present time none have shown clinical success . In addition, toxicological effects induced by various classes of ACAT inhibitors have consistently been observed in the adrenal glands of certain species − and are considered to be dose-limiting effects and thus make the development of ACAT inhibitors more difficult. With respect to the mechanisms of this toxicity, although some reports have been published, 11b-e,13b,, it still remains unclear whether this adrenotoxicity is related to ACAT inhibition 13b,15 or not. 11c,14d-f In our previously reported series, FR182980 showed adrenal toxicity in rabbits and dogs.…”

“…In addition, toxicological effects induced by various classes of ACAT inhibitors have consistently been observed in the adrenal glands of certain species − and are considered to be dose-limiting effects and thus make the development of ACAT inhibitors more difficult. With respect to the mechanisms of this toxicity, although some reports have been published, 11b-e,13b,, it still remains unclear whether this adrenotoxicity is related to ACAT inhibition 13b,15 or not. 11c,14d-f In our previously reported series, FR182980 showed adrenal toxicity in rabbits and dogs. In contrast, drug-related histopathologic alterations to the adrenal glands of rabbits and/or dogs were not observed with the related compounds FR179254, FR186054, and FR180734 (Chart ).…”