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.
A series of N-alkyl-N-[(fluorophenoxy)benzyl]-N'-arylureas were prepared and evaluated for their ability to inhibit intestinal acyl-CoA:cholesterol O-acyltransferase and to inhibit accumulation of cholesteryl esters in macrophages in vitro. In vivo hypocholesterolemic activity was assessed in cholesterol-fed rats by oral administration as a dietary admixture and/or by gavage in a PEG400 vehicle. Modification of the alkyl substituent on the N'-aryl moiety and on the urea nitrogen significantly influenced macrophage assay in vitro. Toxicological study revealed a distinct relationship between macrophage assay and the toxicity observed in adrenal glands of rabbits treated with representatives of this series of compounds. Investigations utilizing the macrophage assay as an indicator for adrenal toxicity led to the identification of compounds 1g (FR190809) and 1k (FR186485, or FR195249 as its hydrochloride salt) as potent, nonadrenotoxic, orally efficacious ACAT inhibitors irrespective of the administration method.
Medicinal Chemistry Research Laboratories, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Company Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
A
A
Tanaka
T
T
Terasawa
H
H
Hagihara
N
N
Ishibe
M
M
Sawada
Y
Y
Sakuma
M
M
Hashimoto
H
H
Takasugi
H
H
Tanaka
D000107:Acetylation; D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D007422:Intestines / Q000201:enzymology; D008077:Lipoproteins, LDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; C115433:FR 186485; D008077:Lipoproteins, LDL; D011725:Pyridines; C115432:FR 190809; D014508:Urea; D002785:Sterol O-Acyltransferase