ACAT inhibitors CL 283,546 and CL 283,796 reduce LDL cholesterol without affecting cholesterol absorption in African green monkeys.

Wrenn, Simeon M.; Parks, John S.; Immermann, Fred; Rudel, Lawrence L.

doi:10.1016/s0022-2275(20)41128-9

Cited by 23 publications

(3 citation statements)

References 59 publications

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“…In the non- N -methylpyrazole series, the best compound 3m was selected for further modification (Table ). Conversion of 2,4,6-trimethylphenyl to 2,4,6-trifluorophenyl, which is one of the standard aromatic rings for ACAT inhibitors, increased both in vitro and in vivo activity ( 3ai ). However, introduction of 2,4-bis(methylthio)-6-methylpyridine, which afforded the best compound FR182980 in our previously reported series, significantly reduced activity ( 3aj ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 1998

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 1998

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“…1). It has been shown in animals that blocking ACAT activity by using various ACAT inhibitors causes a reduction in very low density lipoprotein (VLDL) synthesis and secretion in the liver and/ or cholesterol absorption in the intestines (2)(3)(4). In addi-tion, ACAT may play an important role in the differentiating monocytes and in forming the macrophage foam cells during the development of atherosclerosis (5,6).…”

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confidence: 99%

Immunodepletion experiments suggest that acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines

Lee

Chang

Lee

et al. 1998

Journal of Lipid Research

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The first acyl-coenzyme A:cholesterol acyltransferase (ACAT) cDNA cloned and expressed in 1993 is designated as ACAT-1. In various human tissue homogenates, ACAT-1 protein is effectively solubilized with retention of enzymatic activity by the detergent CHAPS along with high salt. After using anti-ACAT-1 antibodies to quantitatively remove ACAT-1 protein from the solubilized enzyme, measuring the residual ACAT activity remaining in the immunodepleted supernatants allows us to assess the functional significance of ACAT-1 protein in various human tissues. The results showed that ACAT activity was immunodepleted 90% in liver (83% in hepatocytes), 98% in adrenal gland, 91% in macrophages, 80% in kidney, and 19% in intestines, suggesting that ACAT-1 protein plays a major catalytic role in all of the human tissue/cell homogenates examined except intestines. Intestinal ACAT activity is largely resistant to immunodepletion and is much more sensitive to inhibition by the ACAT inhibitor Dup 128 than liver ACAT activity.-Lee, O., C. C. Y. Chang, W. Lee, and T-Y. Chang. Immunodepletion experiments suggest that acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines.

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“…25 Also, its ACAT-catalyzed cholesterol esterification is higher than known inhibitors such as CL-283546. 26 Synthetic preparation of racemic inhibitors starts from 1,3-benzodioxyl derivatives as useful building blocks. Introduction of the CF 3 S group in the early-stage of the synthesis warrants that the final drug shows enhanced lipophilicity.…”

Section: Reagents Used To Introduce the Cf 3 S Group In Medicinal Tar...mentioning

confidence: 99%

Late stage trifluoromethylthiolation strategies for organic compounds

2016

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Substitution by the CF3S group allows for an increase in lipophilicity and electron-withdrawing properties along with an improvement in the bioavailability of medicinal targets; consequently, the late stage introduction of CF3S moieties into medicinal scaffolds is a sought-after strategy in synthetic organic chemistry. Different newly-developed electrophilic and nucleophilic reagents are used to effect the trifluoromethylthiolation of (hetero)aromatic compounds, aliphatic compounds (alkyl, alkenyl, alkynyl substrates), the trifluoromethylthiolation at the α- and β-carbonyl positions, and heteroatoms (N- and S-). Such reactions can involve homolytic substitutions, or functional-group substitutions (ipso). Addition reactions of electrophilic reagents to double and triple bonds followed by ring-cyclizations will be shown to yield relevant CF3S-substituted heteroaromatic compounds with relevant pharmacological action.

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ACAT inhibitors CL 283,546 and CL 283,796 reduce LDL cholesterol without affecting cholesterol absorption in African green monkeys.

Cited by 23 publications

References 59 publications

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

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

Immunodepletion experiments suggest that acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines

Late stage trifluoromethylthiolation strategies for organic compounds

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