Drug Metabolism and Pharmacokinetics of 4-Substituted Methoxybenzoyl-Aryl-Thiazoles (SMART).
Summary of "Drug Metabolism and Pharmacokinetics of 4-Substituted Methoxybenzoyl-Aryl-Thiazoles (SMART)."
Tubulins are one of the oldest and most extensively studied therapeutic targets for cancer. Although many tubulin polymerizing and depolymerizing agents are known, the search for improved agents continues. We screened a class of tubulin targeting small molecules, and identified 4-(3,4,5-trimethoxylbenzoyl)-2-phenyl-thiazole (SMART-H) as our lead compound. SMART-H inhibited the proliferation of a variety of cancer cells in vitro, at sub-nanomolar IC50, and in vivo, in nude mice xenografts, with near 100% tumor growth inhibition. Metabolic stability studies with SMART-H in liver microsomes of four species (mouse, rat, dog, and human) revealed half-lives between < 5 and 30 min, demonstrating an inter-species variability. The clearance predicted based on in vitro data correlated well with in vivo clearance obtained from mouse, rat, and dog in vivo pharmacokinetic studies. SMART-H underwent four major metabolic processes, including ketone reduction, demethylation, combination of ketone reduction and demethylation, and hydroxylation in human liver microsomes. Metabolite identification studies revealed that the ketone and the methoxy groups of SMART-H were most labile, and that ketone reduction was the dominant metabolism reaction in human liver microsomes. We designed and tested four derivatives of SMART-H to improve the metabolic stability. The oxime and hydrazide derivatives, replacing the ketone site, demonstrated a 2-3-fold improved half-life in human liver microsomes, indicating that our prediction regrading metabolic stability of SMART-H can be extended by blocking ketone reduction. These studies led us to the next generation of SMART compounds with greater metabolic stability and higher pharmacologic potency.
1 GTx Inc.;
This article was published in the following journal.
Name: Drug metabolism and disposition: the biological fate of chemicals
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20675405
- DOI: http://dx.doi.org/10.1124/dmd.110.034348
Palladium-catalyzed cross-coupling via the Csp(2)-S bond activation of aryl thioethers and the C-H bond activation of azoles or thiazoles was carried out. Electron-deficient and -rich aryl methyl thio...
The direct arylation of the C4 position of both N-alkyl- and N-arylsydnones with aryl/heteroaryl chlorides has been realized. The reaction is quite general and allows access to a wide range of 4-subst...
The aryl-substituted γ-lactones ralfuranones A and B were isolated after feeding l-[1-(13)C]-phenylalanine to a liquid culture of the plant pathogenic bacterium Ralstonia solanacearum. (13)C NMR anal...
Pregnancy is associated with a variety of physiological changes that can alter the pharmacokinetics and pharmacodynamics of several drugs. However, limited data exists on the pharmacokinetics and phar...
The synthesis of 5-substituted 6,6a-dihydroisoindolo[2,1-a]quinolin-11(5H)-ones via [4 + 2] imino-Diels-Alder cyclization from N-aryl-3-hydroxyisoindolinones and N-vinyl lactams under Lewis acid-catal...
The objective of this study is to prove the safety and efficacy of the Linox smart S DX ICD lead.
Clarithromycin is a potent inhibitor of the activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). CYP 3A4 plays a role in the metabolism of colchicine and P-gp is responsible f...
The study hypothesis is that a modified smart bite block system can deliver up to 10 liters/minute of supplemental oxygen orally with the CO2 monitoring performance substantially equivalen...
Morbid obesity (MO) is associated with several disorders such as hypertension, type 2 diabetes, dyslipemia and degenerative arthropathy that require pharmacological treatment. Drug bioavai...
The purpose of this study is to compare the effects of two different anti-HIV drug regimens on HIV transmission risk behavior among SMART study participants.
Medical and Biotech [MESH] Definitions
Agents that aid or increase the action of the principle drug (DRUG SYNERGISM) or that affect the absorption, mechanism of action, metabolism, or excretion of the primary drug (PHARMACOKINETICS) in such a way as to enhance its effects.
The action of a drug that may affect the activity, metabolism, or toxicity of another drug.
Forms to which substances are incorporated to improve the delivery and the effectiveness of drugs. Drug carriers are used in drug-delivery systems such as the controlled-release technology to prolong in vivo drug actions, decrease drug metabolism, and reduce drug toxicity. Carriers are also used in designs to increase the effectiveness of drug delivery to the target sites of pharmacological actions. Liposomes, albumin microspheres, soluble synthetic polymers, DNA complexes, protein-drug conjugates, and carrier erythrocytes among others have been employed as biodegradable drug carriers.
The properties and processes of drug metabolism and drug interactions.
Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals.