Track topics on Twitter Track topics that are important to you
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
A class of oxalic diamides are found to be effective ligands for promoting CuI-catalyzed aryl amination with less reactive (hetero)aryl chlorides. The reaction proceeds at 120 oC with K3PO4 as the bas...
Although investigations in metabolism and pharmacokinetics of Ranunculales phytometabolites are booming, data obtained from human and animal studies have not been summarized as a whole to outline curr...
Ginkgo leaf tablet (GLT) is an effective traditional Chinese multi-herbal formula, which is often combined with amlodipine for treating senile hypertension in clinic. The aim of this study was to stud...
A novel one-pot [4+2]-benzannulation approach to substituted carbazoles is accomplished by acid-catalyzed C3-propargylation of 2-alkenyl/aryl indoles with 1-aryl propargylic alcohols, followed by cycl...
Moxifloxacin and rifampicin are all the first line options for treatment of active tuberculosis, which are often combined for the treatment of multi-drug resistance pulmonary tuberculosis in clinic. H...
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...
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 objective of this study is to prove the safety and efficacy of the Linox smart S DX ICD lead.
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...
CP-945,598 is eliminated following extensive metabolism. Decrease hepatic function can affect its elimination from the body via metabolism. This study will therefore compare the pharmaco...
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.
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...
Head and neck cancers
Cancer can occur in any of the tissues or organs in the head and neck. There are over 30 different places that cancer can develop in the head and neck area. Mouth cancers (oral cancers) - Mouth cancer can develop on the lip, the tongue, the floor...
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...