Inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT). Part 1: Identification and structure-activity relationships of a novel series of substituted N-alkyl-N-biphenylylmethyl-N′-arylureas

Terasawa, Takeshi; Hagihara, Hiroyuki; Sakuma, Yoh; Ishibe, Noriko; Sawada, Masae; Takasugi, Hisashi; Tanaka, Hirokazu

doi:10.1016/s0968-0896(97)10009-8

Cited by 30 publications

(26 citation statements)

References 49 publications

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“…One of the compounds identified from the screen was a known inhibitor of the host ACAT, FR179254 (Tanaka et al, 1998). A more detailed characterization of its anti-chlamydial activity showed FR179254 at 20 μM to dramatically inhibit growth of the rapidly growing C. trachomatis serovar L2, resulting smaller and less numerous inclusions and lower yields of IFU assay (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

A Functional Slow Recycling Pathway of Transferrin is Required for Growth of Chlamydia

Ouellette

Carabeo

2010

Front. Microbio.

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An inhibitor of host cell lysophospholipid acyltransferase, an enzyme involved in lipid metabolism blocked growth of the obligate intracellular pathogen Chlamydia through its action on the transport of transferrin (Tf) via the slow pathway of recycling. A detailed characterization of this inhibition revealed that Tf accumulated in vesicles positive for Rab11, with a concomitant reduction in the level of Tf found within the transport intermediate Rab4/11 hybrid vesicles. The net result was the failure to be recycled to the plasma membrane. In chlamydiae-infected cells, the Tf-containing Rab11-positive vesicles were typically found intimately associated with the inclusion, and treatment with the inhibitor caused their accumulation, suggesting that the timely progression and completion of Tf recycling was necessary for proper chlamydial growth. Growth inhibition by the compound could be negated by the simple removal of the Tf-containing fraction of the serum, a further indication that accumulation of Tf around the chlamydial inclusion was deleterious to the pathogen. Thus, it appears that manipulating the slow recycling pathway can have biological consequences for Chlamydia and implies the need to regulate carefully the interaction of the inclusion with this host trafficking pathway.

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Section: Resultsmentioning

confidence: 99%

A Functional Slow Recycling Pathway of Transferrin is Required for Growth of Chlamydia

Ouellette

Carabeo

2010

Front. Microbio.

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“…11c,12 As part of our research program directed at the development of potent ACAT inhibitors that are particularly effective in in vivo models of hypercholesterolemia, we have recently investigated and reported on a novel series of N-alkyl-N-(biphenylylmethyl)-N′-arylurea derivatives represented by 1 as a series related to CL 277,082. 13 From this series, FR182980 was identified as a potent ACAT inhibitor in vitro and an efficacious hypocholesterolemic agent in vivo. Due to the encouraging biological results, we have continued our efforts to develop novel ACAT inhibitors and opted to design, prepare, and evaluate the novel series of N-alkyl-N-(heteroaryl-substituted benzyl)-N′-arylureas and related derivatives represented by 2 and 3, replacing one of the phenyl rings of the biphenyl moiety of 1 by a heteroaromatic ring as heterocyclic isosteres of 1, since heterocyclic replacement might be expected to improve physicochemical characteristics such as aqueous solubility and influence biological activity as well as toxicity.…”

Section: Introductionmentioning

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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“…The latter was then brominated in the presence of PBr 3 in CH 2 Cl 2 to give the desired benzylbromide 5b (Lei and Atkinson, 2000) (Scheme 4). Then, the photophore benzophenone 5c was synthesized by a Friedel-Craft acylation of the p-tolylchloride 12 with benzene to give the benzophenone 13 (Smith, 1921), which was brominated with NBS and catalytic dibenzoyl peroxide to afford the benzyl bromide 5c (Tanaka et al, 1998) (Scheme 5).…”

Section: Chemistrymentioning

confidence: 99%

Design, synthesis, molecular modeling, and anti-HIV-1 integrase activity of a series of photoactivatable diketo acid-containing inhibitors as affinity probes

et al. 2009

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The diketo acid (DKA) class of HIV-1 integrase (IN) inhibitors is thought to function by chelating divalent metal ions on the enzyme catalytic site. However, differences in mutations conferring resistance to various DKA inhibitors suggest that multiple binding orientations may exist. In order to facilitate identification of DKA binding sites, a series of photoactivable analogues of two potent DKAs was prepared as novel photoaffinity probes. In cross-linking assays designed to measure disruption of substrate DNA binding, the photoprobes behaved similarly to a reference DKA inhibitor. Molecular modeling studies suggest that such photoprobes interact within the IN active site in a manner similar to that of the parent DKAs. Analogues Ia-c are novel photoaffinity ligands useful in clarifying the HIV-1 binding interactions of DKA inhibitors.

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Inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT). Part 1: Identification and structure-activity relationships of a novel series of substituted N-alkyl-N-biphenylylmethyl-N′-arylureas

Cited by 30 publications

References 49 publications

A Functional Slow Recycling Pathway of Transferrin is Required for Growth of Chlamydia

A Functional Slow Recycling Pathway of Transferrin is Required for Growth of Chlamydia

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

Design, synthesis, molecular modeling, and anti-HIV-1 integrase activity of a series of photoactivatable diketo acid-containing inhibitors as affinity probes

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