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1.
Clin Pharmacol Drug Dev ; 12(9): 911-919, 2023 09.
Article in English | MEDLINE | ID: mdl-37132402

ABSTRACT

When highly purified cannabidiol (CBD; Epidiolex) and the mammalian target of rapamycin inhibitor everolimus are used concomitantly in the treatment of tuberous sclerosis complex, there is evidence of a pharmacokinetic (PK) interaction, leading to increased everolimus systemic exposure. We evaluated the effect of steady-state CBD exposure following multiple clinically relevant CBD doses on everolimus PK in healthy adult participants in a single-center, fixed-sequence, open-label, phase 1 study. All participants received oral everolimus 5 mg on day 1, followed by a 7-day washout. On days 9-17, participants received CBD (100 mg/mL oral solution) at 12.5 mg/kg in the morning and evening. On the morning of day 13, participants also received a single dose of oral everolimus 5 mg. Medications were taken 30 or 45 minutes (morning or evening dose) after starting a standardized meal. Maximum concentration and area under the concentration-time curve (AUC) from time of dosing to the last measurable concentration and extrapolated to infinity, of everolimus in whole blood were estimated using noncompartmental analysis, with geometric mean ratios and 90% confidence intervals for the ratios of everolimus dosed with CBD to everolimus dosed alone. A single dose of everolimus 5 mg was well tolerated when administered with multiple doses of CBD. Log-transformed everolimus maximum concentration, AUC from time of dosing to the last measurable concentration, and AUC extrapolated to infinity values increased by ≈2.5-fold, and everolimus half-life remained largely unchanged in the presence of steady-state CBD relative to everolimus dosed alone. Everolimus blood concentration monitoring should be strongly advised with appropriate dose reduction when coadministered with CBD.


Subject(s)
Cannabidiol , Adult , Humans , Cannabidiol/adverse effects , Everolimus/adverse effects , Healthy Volunteers , Sirolimus/adverse effects , Drug Interactions
2.
Clin Pharmacol Drug Dev ; 10(11): 1279-1289, 2021 11.
Article in English | MEDLINE | ID: mdl-33951339

ABSTRACT

This pharmacokinetic (PK) drug-interaction trial investigated the effects of repeated dosing of a plant-derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the United States and Epidyolex in Europe; 100 mg/mL oral solution) on caffeine clearance via modulation of cytochrome P450 (CYP) 1A2 activity in healthy adults. In this phase 1 open-label, fixed-sequence trial, all subjects received a single 200 mg caffeine dose and placebo on day 1. Subjects then titrated CBD from 250 mg once daily to 750 mg twice daily between days 3 and 11 and took 750 mg CBD twice daily between days 12 and 27. On day 26, subjects received a single 200-mg caffeine dose with their morning CBD dose. Plasma concentrations of caffeine and its CYP1A2-mediated metabolite, paraxanthine, were determined on days 1 and 26 and PK parameters derived using noncompartmental analysis. Safety was monitored throughout. Sixteen subjects enrolled, and 9 completed treatment. When caffeine was administered with steady-state CBD, caffeine exposure increased by 15% for Cmax and 95% for AUC0-∞ , tmax increased from 1.5 to 3.0 hours, and t1/2 increased from 5.4 to 10.9 hours compared with caffeine administered with placebo. Under the same conditions, paraxanthine exposure decreased by 22% for Cmax and increased by 18% for AUC0-∞ , tmax increased from 8.0 to 14.0 hours, and t1/2 increased from 7.2 to 13.7 hours. Overall, there were no unexpected adverse events; diarrhea was most common, and 6 subjects discontinued because of elevated liver transaminases. These data suggest that CBD is an inhibitor of CYP1A2.


Subject(s)
Anticonvulsants/pharmacology , Caffeine/pharmacokinetics , Cannabidiol/pharmacology , Central Nervous System Stimulants/pharmacokinetics , Cytochrome P-450 CYP1A2 Inhibitors/pharmacology , Cytochrome P-450 CYP1A2/metabolism , Drug Interactions , Theophylline/metabolism , Adult , Caffeine/metabolism , Central Nervous System Stimulants/metabolism , Female , Humans , Male , Young Adult
3.
Xenobiotica ; 47(9): 771-777, 2017 Sep.
Article in English | MEDLINE | ID: mdl-27618572

ABSTRACT

1. We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2. Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives. 3. We identified the C2-position as the oxidation site by LC-MS and 1H-NMR and showed that C2-substituted derivatives are no longer AO substrates. 4. In addition to the experimental data, these observations are supported by molecular modelling studies in the human AO protein crystal structure.


Subject(s)
Aldehyde Oxidase/antagonists & inhibitors , Pyrimidines/metabolism , Animals , Humans , Mice , Models, Molecular , Proton Magnetic Resonance Spectroscopy , Structure-Activity Relationship
4.
J Med Chem ; 59(4): 1388-409, 2016 Feb 25.
Article in English | MEDLINE | ID: mdl-26741168

ABSTRACT

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Nuclear Proteins/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Repressor Proteins/antagonists & inhibitors , Caco-2 Cells , Cell Membrane Permeability , Enzyme Inhibitors/pharmacokinetics , Humans , Jumonji Domain-Containing Histone Demethylases/chemistry , Jumonji Domain-Containing Histone Demethylases/metabolism , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Pyrimidinones/pharmacokinetics , Repressor Proteins/chemistry , Repressor Proteins/metabolism
5.
J Med Chem ; 59(3): 1078-101, 2016 Feb 11.
Article in English | MEDLINE | ID: mdl-26796641

ABSTRACT

The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.


Subject(s)
Aminopyridines/pharmacology , Cyclin-Dependent Kinase 8/antagonists & inhibitors , Cyclin-Dependent Kinases/antagonists & inhibitors , Drug Discovery , Small Molecule Libraries/pharmacology , Administration, Oral , Aminopyridines/administration & dosage , Aminopyridines/chemistry , Animals , Biological Availability , Caco-2 Cells , Cyclin-Dependent Kinase 8/metabolism , Cyclin-Dependent Kinases/metabolism , Dogs , Dose-Response Relationship, Drug , Female , Humans , Male , Mice , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Rats , Rats, Wistar , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemistry , Solubility , Structure-Activity Relationship , Xenograft Model Antitumor Assays
6.
J Med Chem ; 58(4): 1717-35, 2015 Feb 26.
Article in English | MEDLINE | ID: mdl-25680029

ABSTRACT

WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Drug Evaluation, Preclinical/methods , Luciferases/antagonists & inhibitors , Pyridines/pharmacology , Small Molecule Libraries/pharmacology , Spiro Compounds/pharmacology , Wnt Signaling Pathway/drug effects , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Biological Assay/methods , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Crystallography, X-Ray , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Luciferases/metabolism , Mice , Models, Molecular , Molecular Structure , Pyridines/administration & dosage , Pyridines/chemistry , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemistry , Spiro Compounds/administration & dosage , Spiro Compounds/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor Assays
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