Excretion, Metabolism, and Pharmacokinetics of 1-(8-(2-Chlorophenyl)-9-(4-Chlorophenyl)-9<i>H</i>-Purin-6-yl)-4-(Ethylamino)Piperidine-4-Carboxamide, a Selective Cannabinoid Receptor Antagonist, in Healthy Male Volunteers

Miao, Zhuang; Sun, Hao; Liras, Jennifer; Prakash, Chandra

doi:10.1124/dmd.111.043273

Cited by 9 publications

(9 citation statements)

References 32 publications

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“…Molecular docking studies of compound 1a with CYP3A4 showed two energetically favored binding clusters (clustered at RMSD 2.0 Å) where either the pyrimidino-piperidine ring ( Fig 2 Panel A) or the terminal N -ethyl moiety ( Fig 2 Panel B) of compound 1a are in proximity to the heme iron of CYP3A4 for aliphatic hydroxylations at the pyrimidino-piperidine ring and N -deethylation reactions, respectively. Other binding clusters that were also energetically favored (1–2 kcal/mol within the lowest-energy binding cluster) but not in an orientation for a typical P450-catalyzed reaction, were not included for analysis, an approach we previously reported [ 23 – 27 ]. For example, the binding pose with the trifluoromethyl moiety of 1a closest to the heme may also be energetically favored, but no common P450-catalyzed reactions are expected.…”

Section: Resultsmentioning

confidence: 99%

Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs

et al. 2018

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Two chemotypes were examined in vitro with CYPs 3A4 and 2C19 by molecular docking, metabolic profiles, and intrinsic clearance deuterium isotope effects with specifically deuterated form to assess the potential for enhancement of pharmacokinetic parameters. The results show the complexity of deuteration as an approach for pharmacokinetic enhancement when CYP enzymes are involved in metabolic clearance. With CYP3A4 the rate limiting step was chemotype-dependent. With one chemotype no intrinsic clearance deuterium isotope effect was observed with any deuterated form, whereas with the other chemotype the rate limiting step was isotopically sensitive, and the magnitude of the intrinsic clearance isotope effect was dependent on the position(s) and extent of deuteration. Molecular docking and metabolic profiles aided in identifying sites for deuteration and predicted the possibility for metabolic switching. However, the potential for an isotope effect on the intrinsic clearance cannot be predicted and must be established by examining select deuterated versions of the chemotypes. The results show how in a deuteration strategy molecular docking, in-vitro metabolic profiles, and intrinsic clearance assessments with select deuterated versions of new chemical entities can be applied to determine the potential for pharmacokinetic enhancement in a discovery setting. They also help explain the substantial failures reported in the literature of deuterated versions of drugs to elicit a systemic enhancement on pharmacokinetic parameters.

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Section: Resultsmentioning

confidence: 99%

Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs

et al. 2018

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“…First, a highly reactive oxonium ion species is generated; this is followed by SN1 nucleophilic attack of a nitrogen or oxygen (Oppenheimer, 1994), with nicotinamide acting as a leaving group. Examples of substrates are rifampin, imatinib (Miao et al, 2012), otenabant, natural toxin 4-ipomeanol (Chen et al, 2006), nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) (Peterson et al, 1994), and 6-(1H-pyrazol-4-yl GSH conjugates are first hydrolyzed by GGT to cysteinylglycine conjugates, which are subsequently further hydrolyzed by amino dipeptidase to cysteine conjugates. These conjugates can be either conjugated by N-acetyl transferase to form mercapturic acids or further cleaved by b-lyase to form possible thiol conjugates (Drug-S 4).…”

Section: Adp-ribosyltransferasementioning

confidence: 99%

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, -Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

Pw¹,

Zhang²,

Js³

et al. 2016

Drug Metabolism and Disposition

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The significant roles that cytochrome P450 (P450) and UDPglucuronosyl transferase (UGT) enzymes play in drug discovery cannot be ignored, and these enzyme systems are commonly examined during drug optimization using liver microsomes or hepatocytes. At the same time, other drug-metabolizing enzymes have a role in the metabolism of drugs and can lead to challenges in drug optimization that could be mitigated if the contributions of these enzymes were better understood. We present examples (mostly from Genentech) of five different non-P450 and non-UGT enzymes that contribute to the metabolic clearance or bioactivation of drugs and drug candidates. Aldehyde oxidase mediates a unique amide hydrolysis of ,7-tetrahydro-1-benzothiophene-2-carboxamide), leading to high clearance of the drug. Likewise, the rodent-specific ribose conjugation by ADP-ribosyltransferase leads to high clearance of an interleukin-2-inducible T-cell kinase inhibitor. Metabolic reactions by flavin-containing monooxygenases (FMO) are easily mistaken for P450-mediated metabolism such as oxidative defluorination of 4-fluoro-N-methylaniline by FMO. Gamma-glutamyl transpeptidase is involved in the initial hydrolysis of glutathione metabolites, leading to formation of proximate toxins and nephrotoxicity, as is observed with cisplatin in the clinic, or renal toxicity, as is observed with efavirenz in rodents. Finally, cathepsin B is a lysosomal enzyme that is highly expressed in human tumors and has been targeted to release potent cytotoxins, as in the case of brentuximab vedotin. These examples of non-P450-and non-UGT-mediated metabolism show that a more complete understanding of drug metabolizing enzymes allows for better insight into the fate of drugs and improved design strategies of molecules in drug discovery.

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“…The derived configuration was further structurally optimized using a quantum mechanicsbased spin-unrestricted B3LYP (Becke, three-parameter, Lee-Yang-Parr) density functional theory method in Gaussian 09 (Gaussian, Inc., Wallingford, CT). A split valence basis set, 6-31G**, in which polarization functions were added on both heavy atoms and hydrogens, was implemented as described previously (Miao et al, 2012;Sun, 2012;Sun et al, 2012). The energetically minimized structure of PF-00734200 by density functional theory was then modified by AutoDockTools (Scripps Research Institute, La Jolla, CA) with Gasteiger atomic charges assigned and flexible torsions defined as the docking input file.…”

Section: Extraction Of Metabolites From Biological Samplesmentioning

confidence: 99%

Metabolism, Excretion, and Pharmacokinetics of ((3,3-Difluoropyrrolidin-1-yl)((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, a Dipeptidyl Peptidase Inhibitor, in Rat, Dog and Human

et al. 2012

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Excretion, Metabolism, and Pharmacokinetics of 1-(8-(2-Chlorophenyl)-9-(4-Chlorophenyl)-9H-Purin-6-yl)-4-(Ethylamino)Piperidine-4-Carboxamide, a Selective Cannabinoid Receptor Antagonist, in Healthy Male Volunteers

Abstract: ABSTRACT:The disposition of 1-(8- (

Cited by 9 publications

References 32 publications

Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs

Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, -Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

Metabolism, Excretion, and Pharmacokinetics of ((3,3-Difluoropyrrolidin-1-yl)((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, a Dipeptidyl Peptidase Inhibitor, in Rat, Dog and Human

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