- CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches
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Lamisil (terbinafine) is an effective, widely prescribed antifungal drug that causes rare idiosyncratic hepatotoxicity. The proposed toxic mechanism involves a reactive metabolite, 6,6-dimethyl-2-hepten-4-ynal (TBF-A), formed through three N-dealkylation pathways. We were the first to characterize them using in vitro studies with human liver microsomes and modeling approaches, yet knowledge of the individual enzymes catalyzing reactions remained unknown. Herein, we employed experimental and computational tools to assess terbinafine metabolism by specific cytochrome P450 isozymes. In vitro inhibitor phenotyping studies revealed six isozymes were involved in one or more N-dealkylation pathways. CYP2C19 and 3A4 contributed to all pathways, and so, we targeted them for steady-state analyses with recombinant isozymes. N-Dealkylation yielding TBF-A directly was catalyzed by CYP2C19 and 3A4 similarly. Nevertheless, CYP2C19 was more efficient than CYP3A4 at N-demethylation and other steps leading to TBF-A. Unlike microsomal reactions, N-denaphthylation was surprisingly efficient for CYP2C19 and 3A4, which was validated by controls. CYP2C19 was the most efficient among all reactions. Nonetheless, CYP3A4 was more selective at steps leading to TBF-A, making it more effective in terbinafine bioactivation based on metabolic split ratios for competing pathways. Model predictions did not extrapolate to quantitative kinetic constants, yet some results for CYP3A4 and CYP2C19 agreed qualitatively with preferred reaction steps and pathways. Clinical data on drug interactions support the CYP3A4 role in terbinafine metabolism, while CYP2C19 remains understudied. Taken together, knowledge of P450s responsible for terbinafine metabolism and TBF-A formation provides a foundation for investigating and mitigating the impact of P450 variations in toxic risks posed to patients.
- Davis, Mary A.,Barnette, Dustyn A.,Flynn, Noah R.,Pidugu, Anirudh S.,Swamidass, S. Joshua,Boysen, Gunnar,Miller, Grover P.
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p. 1151 - 1164
(2019/05/01)
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- Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4N)SCF3
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Reported herein is the one-pot synthesis of trifluoromethylated amines at room temperature using the bench-stable (Me4N)SCF3reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF3with the amine, giving quantitative formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N-CF3. The mildness and high functional group tolerance render the method highly attractive for the late-stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug molecules.
- Scattolin, Thomas,Deckers, Kristina,Schoenebeck, Franziska
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supporting information
p. 221 - 224
(2016/12/30)
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- Expeditious enyne construction from alkynes via oxidative Pd(II)-catalyzed Heck-type coupling
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The enyne, ubiquitous in natural products, can be a challenge to generate since these moieties require many synthetic transformations to assemble them. We developed a simpler protocol to construct enynes while we found that this oxidative reaction was tolerant in substrate scope. In addition, the utility of this reaction was demonstrated through the attempt in synthesizing antifungal agent Lamisil.
- Hadi, Victor,Yoo, Kyung Soo,Jeong, Min,Jung, Kyung Woon
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scheme or table
p. 2370 - 2373
(2009/07/19)
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- Antifungal derivatives of N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine and method of using same
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N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine derivatives are provided having the general formula STR1 wherein R1 is methoxy, iminomethyl or 1-iminoethyl and R2 and R3 are each hydrogen; or R1 is methyl and one of R2 and R3 is hydrogen and the other is halogen. The above compounds as well as acid-addition salts thereof are useful as antifungal agents.
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