Influence of Some Novel N-Substituted Azoles and Pyridines on Rat Hepatic CYP3A Activity

Slama, James T.; Hancock, Julie L.; Rho, Taikyun; Sambucetti, Lidia; Bachmann, Kenneth

doi:10.1016/s0006-2952(98)00096-3

Cited by 22 publications

(15 citation statements)

References 27 publications

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“…Thus, induction response of aminopyrine and erythromycin N-demethylase activities by CLZ was different from clotrimazole administration. Slama et al (1998) have revealed that ethosuximide clearance and in vitro erythromycin N-demethylase activity after treatment with various kinds of N-substituted imidazole derivatives were shown to correlate. Since CLZ also increased erythromycin N-demethylase activity (Fig.…”

Section: Discussionmentioning

confidence: 99%

Climbazole is a new potent inducer of rat hepatic cytochrome P450.

et al. 2001

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We examined the effect of climbazole on the induction of rat hepatic microsomal cytochrome P450 (P450), and compared the induction potency with other N-substituted azole drugs such as clorimazole. We found that climbazole is found to be a potent inducer of rat hepatic microsomal P450 as clorimazole. Induced level of P450 by climbazole was almost similar in extent to clorimazole when compared with other imidazole drugs in a dose-and time-dependent manner. Parallel to the increase in P450, climbazole increased aminopyrine and erythromycin N-demethylase, ethoxycoumarin O-deethylase, and androstenedione 16 and 15 /6 hydroxylase activities; however, clorimazole did not induce aminopyrine N-demethylase activity irrespective of its marked increase in P450 content. Immunoblot analyses revealed that climbazole induced CYP2B1, 3A2 and 4A1. The present findings indicate that climbazole is a new potent inducer of hepatic microsomal P450 and drug-metabolizing enzymes like clorimazole, but it may have some differential mechanism(s) for these enzymes' induction in rat liver.

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Section: Discussionmentioning

confidence: 99%

Climbazole is a new potent inducer of rat hepatic cytochrome P450.

et al. 2001

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“…Clotrimazole was previously reported to be effective in rheumatoid arthritis (15). However, the gastrointestinal and urinary disturbances caused by clotrimazole, coupled with elevation of hepatic enzymes (9,16) and changes in plasma cortisol levels (15) caused by its acute inhibition (2)(3)(4) and chronic induction of human P450-dependent enzymes (3,17), may limit its systemic use (18).…”

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confidence: 99%

Design of a potent and selective inhibitor of the intermediate-conductance Ca²⁺-activated K⁺channel,IKCa1: A potential immunosuppressant

Wulff

Miller

Hänsel

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

567

642

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The antimycotic clotrimazole, a potent inhibitor of the intermediate-conductance calcium-activated K ؉ channel, IKCa1, is in clinical trials for the treatment of sickle cell disease and diarrhea and is effective in ameliorating the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by clotrimazole limits its therapeutic value. We have used a rational design strategy to develop a clotrimazole analog that selectively inhibits IKCa1 without blocking cytochrome P450 enzymes. A screen of 83 triarylmethanes revealed the pharmacophore for channel block to be different from that required for cytochrome P450 inhibition. The ''IKCa1-pharmacophore'' consists of a (2-halogenophenyl)diphenylmethane moiety substituted by an unsubstituted polar -electron-rich heterocycle (pyrazole or tetrazole) or a ؊C'N group, whereas cytochrome P450 inhibition absolutely requires the imidazole ring. A series of pyrazoles, acetonitriles, and tetrazoles were synthesized and found to selectively block IKCa1. TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole) inhibits the cloned and the native

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“…10) With a high affinity toward the heme group, azole drugs form covalent irreversible bonds that translate into a high toxicity. 11) An alternative and promising strategy replaces covalent with electrostatic binding by introducing hydrophobic and bioisosteric groups that interact strongly with hydrophobic residues in the cavities of the CYP51 active site. The challenge, then, is to identify ancillary groups that enhance binding and inhibition without promoting covalent bond formation.…”

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confidence: 99%

<i>De Novo</i> Design of Non-coordinating Indolones as Potential Inhibitors for Lanosterol 14-α-Demethylase (CYP51)

González-Chávez

Martı́nez

Torre-Bouscoulet

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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The development of antifungal drugs that inhibit lanosterol 14-α-demethylase (CYP51) via non-covalent ligand interactions is a strategy that is gaining importance. A series of novel tetraindol-4-one derivatives with 1-and 2-(2,4-substituted phenyl) side chains were designed and synthesized based on the structure of CYP51 and fluconazole. The antifungal activities of these derivatives against eight human pathogenic filamentous fungi and yeast strains were evaluated in vitro by measuring the minimal inhibitory concentrations. Nearly all tested compounds 8a-g displayed activity against Candida tropicalis, Candida guilliermondii and Candida parapsilosis with a minimum inhibitory concentration (MIC) value until 8 µg mL 1 , on the other hand compounds 7a-g showed activity against Aspergillus fumigatus with a MIC value of 31.25 µg mL 1 . A molecular modeling study of the binding interactions between compounds 6, 7d, 8g and the active site of MtCYP51 was conducted based on the computational docking results.

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Influence of Some Novel N-Substituted Azoles and Pyridines on Rat Hepatic CYP3A Activity

Cited by 22 publications

References 27 publications

Climbazole is a new potent inducer of rat hepatic cytochrome P450.

Climbazole is a new potent inducer of rat hepatic cytochrome P450.

Design of a potent and selective inhibitor of the intermediate-conductance Ca²⁺-activated K⁺channel,IKCa1: A potential immunosuppressant

<i>De Novo</i> Design of Non-coordinating Indolones as Potential Inhibitors for Lanosterol 14-α-Demethylase (CYP51)

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Influence of Some Novel N-Substituted Azoles and Pyridines on Rat Hepatic CYP3A Activity

Cited by 22 publications

References 27 publications

Climbazole is a new potent inducer of rat hepatic cytochrome P450.

Climbazole is a new potent inducer of rat hepatic cytochrome P450.

Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+channel,IKCa1: A potential immunosuppressant

<i>De Novo</i> Design of Non-coordinating Indolones as Potential Inhibitors for Lanosterol 14-α-Demethylase (CYP51)

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Design of a potent and selective inhibitor of the intermediate-conductance Ca²⁺-activated K⁺channel,IKCa1: A potential immunosuppressant