Specific inhibitors of Human UDP-Glucuronosyltransferases Enhance the Efficacy of Selected Antivirals by Changing their Pharmacokinetic Profiles

Application: UDP-glucuronosyltransferase (UGT) inhibitors for different UGT’s significantly reduce the systemic clearance rates of selected antivirals drugs, thus when used in combination with other drugs these UGT inhibitors act to significantly enhance efficacy antiviral therapeutics that require UGT’s for their systemic clearance.

Human UGTs are extensively involved in the overall metabolism and disposition of endo- and xenobiotics and work in combination with cytochromes P-450 to regulate the systemic turnover of drugs.

Different human hepatic and extrahepatic UGTs are involved in the glucuronidation of physiologically important substrates and drugs. Modulation of these UGT activities by either inhibition or induction will alter the biotransformation of endogenous metabolites, active pharmaceutical ingredients and their rates of disposition.

This invention describes a family of eight different compounds that act as inhibitors of UGT’s that are able to alter many pharmacological effecter molecules. Each of these novel compounds impact the pharmacokinetic properties of active pharmaceutical ingredients that are administered with them. These eight UGT specific compounds contain a lipophilic N-acyl phenylaminoalcohol residue and a uridine moiety connected by a spacer of different lengths (PP-inhibitors). These compounds have been synthesized and successfully applied to the inhibition of several UGTs from the different UGT families that are involved in the glucuronidation of several different drugs. These novel compounds play a very important role in the inhibition of different UGT’s which in turn can have profound effects on the pharmacokinetic properties of selected drugs and metabolites.

This invention is a new approach to control of the pharmacokinetic behavior of active pharmaceutical ingredients. Until this point no specific UGT inhibitors were available to slow glucuronidation and turnover of specific drugs.

Future research will involve validating the activity/toxicity of these compounds in vivo.

This invention has high commercial potential as a complimentary drug for many inhibition applications, such as inhibition of the metabolic isoenzyme, UDP-Glucuronosyltransferase-2B7 (UGT2B7), during zidovudine (AZT) treatment of human immunodeficiency virus (HIV).

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09-24 Radominska

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File Number: 09-24 

Web site: http://www.uams.edu/bioventures

Disease: Infectious Diseases

Other Information:

One combination that has demonstrated promising results include an inhibitor of the metabolic UGT isoenzyme, UDP-Glucuronosyltransferase-2B7 (UGT2B7), during zidovudine (AZT) treatment for human immunodeficiency virus (HIV).