Design and synthesis of substituted imidazole and triazole <i>N</i>-phenylbenzo[<i>d</i>]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26

Pautus, S.; Aboraia, Ahmed S.; Bassett, Claire E.; Brancale, Andrea; Coogan, Michael P.; Simons, Claire

doi:10.1080/14756360802218334

Cited by 7 publications

(5 citation statements)

References 20 publications

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“…Cyclization of the isocyanate (12) to form the benzoxazole (13) and benzothiazole (14) was achieved by reaction with 2-aminophenol and 2-aminothiophenol, in the presence of mercury oxide and catalytic sulfur (Scheme 1). 22 Introduction of the imidazole to give the required products 15À21 and 23 and 24 involved reaction with carbonyldiimidazole (CDI) and imidazole following described methodology, 18,23 with subsequent purification by column chromatography (Scheme 1). The 6-hydroxy-2-naphthyl product (22) was obtained by demethylation of the corresponding 6-methoxy-2naphthyl imidazole compound (21) (Scheme 1)…”

Section: ' Resultsmentioning

confidence: 99%

“…The 1-naphthyl ( 18), 2-naphthyl (20), benzoxazole (23), and benzothiazole (24) derivatives were evaluated for their inhibitory activity against a panel of P450 isoforms expressed in human liver microsomes (Table 4). The 1-naphthyl (18) and benzoxazole (23) derivatives were highly active against CYP3A4, and the bezothiazole derivative (24) was highly active against CYPs 2C9 and 2C19 at concentrations of 0.4 μM. At this concentration, the 2-naphthyl derivative (20) was either inactive or displayed borderline percent inhibition against the CYP panel.…”

Section: ' Resultsmentioning

confidence: 99%

“…1 H NMR (DMSO-d 6 ): δ 1.22 (s, 6H, H-4, H-5), 3.57 (s, 3H, H-1), 3.89 (s, 3H, OCH 3 ), 5.60 (s, 1H, H-6), 6.85 (s, 1H, Ar), 7.18 (m, 3H, Ar), 7.20 (s, 1H, H-3 000 ), 7.24 (d, J = 7.8 Hz, 1H, Ar), 7.29 (d, J = 7.7 Hz, 2H, H-2 0 , H-6 0 ), 7.41 (s, 1H, H-2 000 ), 7.45 (s, 1H, H-1 000 ), 7.61 (d, J = 8.2 Hz, 1H, H-4 00 ), 7.69 (d, J = 8.3 Hz, 1H, H-9 00 ), 7.82 (s, 1H, H-2 00 ), 8.33 (s, 1H, NH). 13 3-[4-(Benzooxazol-2-ylamino)-phenyl]-3-imidazol-1-yl-2,2-dimethylpropionic Acid Methyl Ester (23). Prepared by the reaction of 13 with CDI and imidazole.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Small Molecule Inhibitors of Retinoic Acid 4-Hydroxylase (CYP26): Synthesis and Biological Evaluation of Imidazole Methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates

et al. 2011

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The synthesis and potent inhibitory activity of novel imidazole methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates in a MCF-7 CYP26A1 microsomal assay is described. The induction of CYP26A1 mRNA was used to evaluate the ability of the compounds to enhance the biological effects of all-trans retinoic acid (ATRA) in a retinoid-responsive neuroblastoma cell line. The most promising inhibitor, 3-imidazol-1-yl-2-methyl-3-[4-(naphthalen-2-ylamino)-phenyl]-propionic acid methyl ester (20), with an IC(50) of 3 nM (compared with liarozole IC(50) of 540 nM and R116010 IC(50) of 10 nM) was further evaluated for CYP selectivity using a panel of CYP enzymes, mutagenicity (Ames screen), and hepatic stability.

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Section: ' Resultsmentioning

confidence: 99%

Section: ' Resultsmentioning

confidence: 99%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Small Molecule Inhibitors of Retinoic Acid 4-Hydroxylase (CYP26): Synthesis and Biological Evaluation of Imidazole Methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates

et al. 2011

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“…It showed much better CYP26A1 inhibitory efficacy (IC 50 = 0.9 μM) than liarozole (IC 50 = 7 μM). Comparative study discovered that the replacement of benzoxazole moiety by phenyl or methyl group or the substitution of imidazolyl group by triazole or tetrazole moiety would decrease the inhibitory efficacy …”

Section: Imidazoles As Anticancer Agentsmentioning

confidence: 99%

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

et al. 2013

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Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.

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“…The first set of compounds with the lead compound 6 (Figure 5) in this series had micromolar inhibitory potency towards CYP26A1 when tested in ATRA induced MCF-7 cells (Table 3) [171]. Upon further optimization, potency was improved by changing the benzofuran moiety to a naphthalene, benzoimidazole or benzooxazole and by adding a benzyl linker between the imidazole moiety and the benzofuran group (compounds 7 and 8, Figure 5) [172, 173]. N -{4-[1 H -Imidazol-1-yl(phenyl)methyl]phenyl}-naphthalen-2-amine (compound 8) was identified as a lead compound (IC 50 = 0.5 μM, in MCF-7 whole cells pretreated with ATRA) together with the benzoimidazole and benzooxazol (compound 7) analogs of this compounds (IC 50 =1.5 and 0.9 μM in MCF-7 cells, respectively) (Figure 5 and Table 3) [173].…”

Section: Pharmacological Effects Of Inhibitors Of Retinoic Acid Hymentioning

confidence: 99%

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

Nelson¹,

Buttrick²,

Isoherranen³

2013

CTMC

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Retinoic acid (RA), the active metabolite of vitamin A, is an important endogenous signaling molecule regulating cell cycle and maintenance of epithelia. RA isomers are also used as drugs to treat various cancers and dermatological diseases. However, the therapeutic uses of RA isomers are limited due to side effects such as teratogenicity, and resistance to treatment emerging mainly from autoinduction of RA metabolism. To improve the therapeutic usefulness of retinoids, RA metabolism blocking agents (RAMBAs) have been developed. These inhibitors generally target the cytochrome P450 (CYP) enzymes because RA clearance is predominantly mediated by P450s. Since the initial identification of inhibitors of RA metabolism, CYP26 enzymes have been characterized as the main enzymes responsible for RA clearance. This makes CYP26 enzymes an attractive target for the development of novel therapeutics for cancer and dermatological conditions. The basic principle of development of CYP26 inhibitors is that endogenous RA concentrations will be increased in the presence of a CYP26 inhibitor, thus, potentiating the activity of endogenous RA in a cell-type specific manner. This will reduce side effects compared to administration of RA and allow for more targeted therapy. In clinical trials, inhibitors of RA metabolism have been effective in treatment of psoriasis and other dermatological conditions as well as in some cancers. However, no CYP26 inhibitor has yet been approved for clinical use. This review summarizes the history of development of RAMBAs, the clinical and preclinical studies with the various structural series and the available knowledge of structure activity relationships of CYP26 inhibitors.

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Design and synthesis of substituted imidazole and triazole N-phenylbenzo[d]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26

Cited by 7 publications

References 20 publications

Small Molecule Inhibitors of Retinoic Acid 4-Hydroxylase (CYP26): Synthesis and Biological Evaluation of Imidazole Methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates

Small Molecule Inhibitors of Retinoic Acid 4-Hydroxylase (CYP26): Synthesis and Biological Evaluation of Imidazole Methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

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