Inhibitors of Acyl-CoA:Cholesterol O-Acyltransferase. 2. Identification and Structure−Activity Relationships of a Novel Series of N-Alkyl-N-(heteroaryl-substituted benzyl)-N‘-arylureas

Q1 · MEDICINE

Article

Author: Tanaka, Akira ; Ishibe, Noriko ; Sawada, Masae ; Tanaka, Hirokazu ; Takasugi, Hisashi ; Hagihara, Hiroyuki ; Sakuma, Yuri ; Terasawa, Takeshi

A series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylurea and related derivatives represented by 2 and 3 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Among these novel compounds, the type 3 series was superior. A pyrazol-3-yl group on the N-benzyl group of this trisubstituted urea (i.e. 3, Ar1 = pyrazol-3-yl) was identified as a heteroaromatic ring providing a good profile of biological activity. As a result of optimization of the combination with the N-alkyl group (R) and N-aryl group (Ar3), compound 3aq (FR186054) was identified as a new, orally efficacious ACAT inhibitor, which exhibited potent in vitro ACAT inhibitory activity (rabbit intestinal microsomes IC50 = 99 nM) and excellent hypocholesterolemic effects in cholesterol-fed rats, irrespective of administration mode (ED50 = 0.046 mg/kg dosed via the diet, ED50 = 0. 44 mg/kg administered by gavage in PEG400 vehicle). Moreover, a toxicological study revealed compound 3aq to be nontoxic to the adrenal glands of dogs when tested at a single dose of 10 mg/kg po.

01 Jan 1998·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Synthesis, X-ray crystal structure, and biological activity of FR186054, a novel, potent, orally active inhibitor of acyl-CoA:cholesterol O -acyltransferase (ACAT) bearing a pyrazole ring

Q4 · MEDICINE

Article

Author: Akira Tanaka ; Takayoshi Kinoshita ; Masae Sawada ; Hiroyuki Hagihara ; Noriko Ishibe ; Hisashi Takasugi ; Yuri Sakuma ; Hirokazu Tanaka ; Takeshi Terasawa

The synthesis, single crystal X-ray structural analysis, and biological activity of FR186054 (2c), a new, potent, orally efficacious inhibitor of acyl-CoA:cholesterol O-acyltransferase (ACAT), containing a pyrazole ring are described. This compound displayed excellent in vitro efficacy, irrespective of dosing method, indicating superior characteristics compared to other ACAT inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Discovery	JP	Fujisawa Pharmaceutical Co., Ltd.	-
Hypercholesterolemia	Discovery	JP	Fujisawa Pharmaceutical Co., Ltd.	-

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