Metabolism of (<i>S</i>)-5,6-Difluoro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4-dihydro-2(1<i>H</i>)-quinazolinone, a Non-Nucleoside Reverse Transcriptase Inhibitor, in Human Liver Microsomes. Metabolic Activation and Enzyme Kinetics

Chen, Hao; Chen, Weiqi; Gan, Liang‐Shang; Mutlib, Abdul

doi:10.1124/dmd.31.1.122

Cited by 20 publications

(23 citation statements)

References 11 publications

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“…21 However, the potential metabolic liability of the acetylenic bond in compound 4 , which may be oxidized to generate a labile, highly reactive oxirene, thereby possibly giving rise to toxicity, discouraged further advancement of this compound down the drug discovery pipeline. 22 Novel ligands were, therefore, designed to avoid the acetylene function while maintaining the important pharmacophoric elements of compound 4 . For various reasons, we considered replacement of the acetylene by a small and rigid cyclopropane ring.…”

Section: Rational Design and Synthesis Of Chiral Cyclopropane Nachr Lmentioning

confidence: 99%

Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile

et al. 2012

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Despite their discovery in the early 20th century and intensive study over the last twenty years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4β2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity, while acting as partial agonists at α4β2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening towards other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4β2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.

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Section: Rational Design and Synthesis Of Chiral Cyclopropane Nachr Lmentioning

confidence: 99%

Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile

et al. 2012

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“…25 Such an internal diarylacetylene functionality is chemically 26 and metabolically stable. 27 For example diarylacetylene moieties are embedded in certain antibiotic drugs. 28,29 These are LpxC inhibitors such as CHIR-090 28 .…”

mentioning

confidence: 99%

Storage of Hydrogen Spin Polarization in Long-Lived ¹³C₂ Singlet Order and Implications for Hyperpolarized Magnetic Resonance Imaging

et al. 2013

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Hyperpolarized magnetic resonance imaging is a powerful technique enabling real time monitoring of metabolites at concentration levels not accessible by standard MRI techniques. A considerable challenge this technique faces is the T1 decay of the hyperpolarization upon injection into the system under study. Here we show that AnA’nXX’ spin systems such as 13C2-1,2-diphenylacetylene (13C2-DPA) sustain long-lived polarization for both 13C and 1H spins with decay constants of almost 4.5 min at high magnetic fields of up to 16.44 T without spin-locking; the T1 of proton polarization is only 3.8 s. Therefore, storage of the proton polarization in a 13C2-singlet state causes a 69 fold extension of the spin lifetime. Notably, this extension is demonstrated with proton-only pulse sequences, which can be readily implemented on standard clinical scanners.

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“…It is also important to note that clarithromycin, a known inhibitor of CYP3A in the gut wall and the liver (Gorski et al, 1998), had little effect on the elimination of efavirenz in healthy volunteers [Product Information of Efavirenz (Sustiva), Bristol-Myers Squibb Company, April 2002]. Recently, Chen et al (2003) have shown that CYP2B6 is the principal catalyst of the in vitro metabolism of DPC 963, another non-nucleoside reverse transcriptase inhibitor that is structurally similar to efavirenz. All these data suggest that P450s (most likely CYP2B6) other than CYP3A might be responsible for the human metabolism of efavirenz.…”

mentioning

confidence: 99%

The Cytochrome P450 2B6 (CYP2B6) Is the Main Catalyst of Efavirenz Primary and Secondary Metabolism: Implication for HIV/AIDS Therapy and Utility of Efavirenz as a Substrate Marker of CYP2B6 Catalytic Activity

Ward

Gorski

Jones³

et al. 2003

J Pharmacol Exp Ther

531

494

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We used human liver microsomes (HLMs) and recombinant cytochromes P450 (P450s) to identify the routes of efavirenz metabolism and the P450s involved. In HLMs, efavirenz undergoes primary oxidative hydroxylation to 8-hydroxyefavirenz (major) and 7-hydroxyefavirenz (minor) and secondary metabolism to 8,14-dihydroxyefavirenz. The formation of 8-hydroxyefavirenz in two HLMs showed sigmoidal kinetics (average apparent K m , 20.2 M; V max , 140 pmol/min/mg protein; and Hill coefficient, 1.5), whereas that of 7-hydroxyefavirenz formation was characterized by hyperbolic kinetics (K m , 40.1 M and V max , 20.5 pmol/min/mg protein). In a panel of 10 P450s, CYP2B6 formed 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz from efavirenz (10 M) at the highest rate. The K m value for the formation of 8-hydroxyefavirenz in CYP2B6 derived from hyperbolic Eq. 12.4 M) was close to that obtained in HLMs (K m , 20.2 M). None of the P450s tested showed activity toward 7-hydroxylation of efavirenz. When 8-hydroxyefavirenz (2.5 M) was used as a substrate, 8,14-dihydroxyefavirenz was formed by CYP2B6 at the highest rate, and its kinetics showed substrate inhibition (K si , ϳ94 M in HLMs and ϳ234 M in CYP2B6). In a panel of 11 HLMs, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz formation rates from efavirenz (10 M) correlated significantly with the activity of CYP2B6 and CYP3A. N,NЈ,NЉ-Triethylenethiophosphoramide (thioTEPA; 50 M) inhibited the formation rates of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz from efavirenz (10 M) by Ն60% in HLMs) and CYP2B6, with K i values Ͻ 4 M. In conclusion, CYP2B6 is the principal catalyst of efavirenz sequential hydroxylation. Efavirenz systemic exposure is likely to be subject to interindividual variability in CYP2B6 activity and to drug interactions involving this isoform. Efavirenz may be a valuable phenotyping tool to study the role of CYP2B6 in human drug metabolism.

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Metabolism of (S)-5,6-Difluoro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4-dihydro-2(1H)-quinazolinone, a Non-Nucleoside Reverse Transcriptase Inhibitor, in Human Liver Microsomes. Metabolic Activation and Enzyme Kinetics

Abstract: This article is available online at http://dmd.aspetjournals.org

Cited by 20 publications

References 11 publications

Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile

Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile

Storage of Hydrogen Spin Polarization in Long-Lived ¹³C₂ Singlet Order and Implications for Hyperpolarized Magnetic Resonance Imaging

The Cytochrome P450 2B6 (CYP2B6) Is the Main Catalyst of Efavirenz Primary and Secondary Metabolism: Implication for HIV/AIDS Therapy and Utility of Efavirenz as a Substrate Marker of CYP2B6 Catalytic Activity

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Metabolism of (S)-5,6-Difluoro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4-dihydro-2(1H)-quinazolinone, a Non-Nucleoside Reverse Transcriptase Inhibitor, in Human Liver Microsomes. Metabolic Activation and Enzyme Kinetics

Abstract: This article is available online at http://dmd.aspetjournals.org

Cited by 20 publications

References 11 publications

Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile

Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile

Storage of Hydrogen Spin Polarization in Long-Lived 13C2 Singlet Order and Implications for Hyperpolarized Magnetic Resonance Imaging

The Cytochrome P450 2B6 (CYP2B6) Is the Main Catalyst of Efavirenz Primary and Secondary Metabolism: Implication for HIV/AIDS Therapy and Utility of Efavirenz as a Substrate Marker of CYP2B6 Catalytic Activity

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Storage of Hydrogen Spin Polarization in Long-Lived ¹³C₂ Singlet Order and Implications for Hyperpolarized Magnetic Resonance Imaging