Fluorine Substitution Can Block CYP3A4 Metabolism-Dependent Inhibition:  Identification of (<i>S</i>)<i>-N</i>-[1-(4-Fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an Orally Bioavailable KCNQ2 Opener Devoid of CYP3A4 Metabolism-Dependent Inhibition

Wu, Yong‐Jin; Davis, Carl D.; Dworetzky, Steven I.; Fitzpatrick, William; Harden, David G.; He, Huan; Knox, Ronald J.; Newton, Amy; Philip, Thomas; Polson, Craig; Sivarao, Digavalli V.; Sun, Li‐Qiang; Tertyshnikova, Svetlana; Weaver, David T.; Yeola, Suresh; Zoeckler, Mary; Sinz, Michael

doi:10.1021/jm034111v

Cited by 60 publications

(33 citation statements)

References 9 publications

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“…Pharmacophore, tree models, and the logistic regression model were tested with molecules outside of the training set using recently published data for 12 compounds (Yamazaki and Shimada, 1998;Kasahara et al, 2000;Kim et al, 2001;Kajita et al, 2002;Chatterjee and Franklin, 2003;Wu et al, 2003) with MIC formation for CYP3A4.…”

Section: Methodsmentioning

confidence: 99%

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Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

Jones¹,

Ekins²,

Li³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Some mechanism-based inhibitors cause irreversible inhibition by forming a metabolic intermediate complex (MIC) with cytochrome P450. In the present study, 54 molecules (substrates of CYP3A and amine-containing compounds that are not known substrates of CYP3A) were spectrophotometrically assessed for their propensity to cause MIC formation with recombinant CYP3A4 (؉b 5 ). Comparisons of common physicochemical properties showed that mean (؎S.D.) mol. wt. of MIC-forming compounds was significantly greater than mean mol. wt. of non-MIC-forming compounds, 472 (؎173) versus 307 (؎137), respectively. Computational pharmacophores, logistic regression, and recursive partitioning (RP) approaches were applied to predict MIC formation from molecular structure and to generate a quantitative structure activity relationship. A pharmacophore built with SKF-525A (2-diethylaminoethyl 2:2-diphenylvalerate hydrochloride), erythromycin, amprenavir, and norverapamil indicated that four hydrophobic features and a hydrogen bond acceptor were important for these MIC-forming compounds. Two different RP methods using either simple descriptors or 2D augmented atom descriptors indicated that hydrophobic and hydrogen bond acceptor features were required for MIC formation. Both of these RP methods correctly predicted the MIC formation status with CYP3A4 for 10 of 12 literature molecules in an independent test set. Logistic multiple regression and a third classification tree model predicted 11 of 12 molecules correctly. Both models possessed a hydrogen bond acceptor and represent an approach for predicting CYP3A4 MIC formation that can be improved using more data and molecular descriptors. The preliminary pharmacophores provide structural insights that complement those for CYP3A4 inhibitors and substrates.

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Section: Methodsmentioning

confidence: 99%

“…This type of screen is useful for identifying potential inhibition of coadministered drugs and is commonly followed by time-dependent inhibition studies (Wu et al, 2003). These studies may be supplemented with additional in vitro assays with more traditional drug substrate probes using liquid chromatography/mass spectrometry analysis (Ekins et al, 2000b).…”

mentioning

confidence: 99%

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

Jones¹,

Ekins²,

Li³

et al. 2007

Drug Metab Dispos

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“…For example compound (95) with its benzo-[1,3]dioxole ring system had an EC 50 value of 6 nM while compound (96) containing the larger dihydro-2H-benzo- [1,4]oxazine system was also very potent with an EC 50 value of 9 nM. Addition of a fluorine at the R3 position was tolerated and was later reported to be beneficial from a metabolism standpoint [103]. Further chemistry indicated that the addition of a hydroxyl functionality to the terminus of themethyl group (compounds 99-101, Table 12) was tolerated [104].…”

Section: Cinnamide Derivatives and Analoguesmentioning

confidence: 99%

Kv7 Channels as Targets for the Treatment of Pain

Wickenden¹,

McNaughton‐Smith²

2009

CPD

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Kv7.x channels are a family of six transmembrane domain, single pore-loop, voltage-gated K(+) channels. Five members of the family have been identified to date, including the cardiac channel Kv7.1 (formerly known as KvLQT1) and four neuronal Kv7.x channels, Kv7.2-5. Heteromeric channels containing Kv7.3 and either Kv7.2 or Kv7.5 are thought to underlie the neuronal M-current, a non-inactivating, slowly deactivating, sub-threshold current that has long been known to exert a powerful stabilizing influence on neuronal excitability. Modulators of these channels have the potential to influence neuronal activity in various tissues and are of much interest as therapeutic drug targets for the treatment of a variety of clinical disorders, such as epilepsy and pain. The purpose of the present article is to review the molecular, functional and behavioral evidence validating Kv7.x as drug targets for the treatment of pain. In addition, an update on pre-clinical Kv7 drug discovery efforts will be presented, along with a summary of on-going clinical trials with Kv7 channel activators.

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“…3). Structure-metabolism dependent inhibition (MDI) relationship studies resulted in the discovery of a difluoro analog of 1 (4) as an orally bioavailable KCNQ2 opener free of CYP3A4 MDI [79]. Another example where metabolite identification at early stages helped the chemists with the design of a safer drug candidate included the discovery of a potent and selective cycloxygenase-2 inhibitor, L-768,277 [80].…”

Section: Mass Spectrometry In Studies Of Drug Biotransformation (Metamentioning

confidence: 99%

High Performance Liquid Chromatography/Atmospheric Pressure Ionization/Tandem Mass Spectrometry (HPLC/API/MS/MS) in Drug Metabolism and Toxicology

Kamel¹,

Prakash²

2006

CDM

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Studies of the metabolic fate of drugs and other xenobiotics in living systems may be divided into three broad areas: (1) elucidation of biotransformation pathways through identification of circulatory and excretory metabolites (qualitative studies); (2) determination of pharmacokinetics of the parent drug and/or its primary metabolites (quantitative studies); and (3) identification of chemically-reactive metabolites, which play a key role as mediators of drug-induced toxicities (mechanistic studies). Mass spectrometry has been regarded as one of the most important analytical tools in studies of drug metabolism, pharmacokinetics and biochemical toxicology. With the commercial introduction of new ionization methods such as those based on atmospheric pressure ionization (API) techniques and the combination of liquid chromatography-mass spectrometry (LC-MS), it has now become a truly indispensable technique in pharmaceutical research. Triple stage quadrupole and ion trap mass spectrometers are presently used for this purpose, because of their sensitivity and selectivity. API-TOF mass spectrometry has also been very attractive due to its enhanced full-scan sensitivity, scan speed, improved resolution and ability to measure the accurate masses for protonated molecules and fragment ions. This review aims to survey the utility of mass spectrometry in drug metabolism and toxicology and to highlight novel applications and future trends in this field.

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Fluorine Substitution Can Block CYP3A4 Metabolism-Dependent Inhibition: Identification of (S)-N-[1-(4-Fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an Orally Bioavailable KCNQ2 Opener Devoid of CYP3A4 Metabolism-Dependent Inhibition

Cited by 60 publications

References 9 publications

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

Kv7 Channels as Targets for the Treatment of Pain

High Performance Liquid Chromatography/Atmospheric Pressure Ionization/Tandem Mass Spectrometry (HPLC/API/MS/MS) in Drug Metabolism and Toxicology

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Fluorine Substitution Can Block CYP3A4 Metabolism-Dependent Inhibition: Identification of (S)-N-[1-(4-Fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an Orally Bioavailable KCNQ2 Opener Devoid of CYP3A4 Metabolism-Dependent Inhibition

Cited by 60 publications

References 9 publications

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b5)

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b5)

Kv7 Channels as Targets for the Treatment of Pain

High Performance Liquid Chromatography/Atmospheric Pressure Ionization/Tandem Mass Spectrometry (HPLC/API/MS/MS) in Drug Metabolism and Toxicology

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Product

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Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)