Improving Absorption and Targeting of Antiviral Drugs

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$3,000,000.00
Award Year:
2007
Program:
SBIR
Phase:
Phase II
Contract:
2R44AI056864-03A1
Award Id:
66050
Agency Tracking Number:
AI056864
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
TSRL, INC., 540 AVIS DR, STE A, ANN ARBOR, MI, 48108
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
156551699
Principal Investigator:
JOHN HILFINGER
(734) 663-4233
JHILFINGER@TSRLINC.COM
Business Contact:
JOHN HILFINGER
() -
jhilfinger@tsrlinc.com
Research Institution:
n/a
Abstract
DESCRIPTION (provided by applicant): With recent unsettling events foreshadowing an increased sense of urgency, NIAID has targeted research and development of therapeutics, vaccines, adjuvants/immunostimulants, and diagnostics for smallpox (variola). TSRL was granted a Phase I SBIR to explore prodrug strategies to increase the oral availability of potential anti-smallpox drugs. Strategies that can improve the oral bioavailability of approved drugs as well as potential drug candidates will facilitate the dev elopment of more effective antiviral agents and reduce undesirable outcomes such as drug toxicity, poor patient compliance, and high costs. The long-term goal of this project for biodefense is to improve the oral absorption of potent, but poorly absorbed a nti-pox agents by designing prodrugs targeted to transporters expressed in human intestine and able to be activated by endogenous esterases or amidases that release the absorbed drug in vivo from its prodrug form. For this project, we established collabora tions with Prof. Charles McKenna (prodrug design and synthesis) at the University of Southern California and Prof. John Drach (virological studies) at the University of Michigan. The work in the Phase I project focused chiefly on prodrugs of cyclic cidofov ir (cHPMPC), a broad spectrum antiviral compound with potent activity against variola and other orthopox viruses, but of limited value in a smallpox epidemic due to its very low oral bioavailability. We demonstrated that dipeptide prodrugs of cHPMPC, which were first discovered in Prof. McKenna's laboratory, have great potential for oral delivery. Our results from an animal oral bioavailability model indicate that absorption of the first generation of dipeptide prodrugs is up to an order of magnitude greate r than that of the parent drug cHPMPC, and that a significant fraction of the absorbed prodrug is converted to drug in vivo. In this Phase II SBIR proposal, we have devised a synthetic strategy and SAR plan to optimize the bioavailability of this new class of prodrug. We have formed a collaborative network of researchers and specialists that will allow us to systematically test a diverse library of novel cHPMPC dipeptide conjugates for stability, transport, drug oral bioavailability, and efficacy in accepte d animal models. The compound or compounds showing the best oral absorption and efficacy will be manufactured following GMP requirements and tested for toxicity. The combined portfolio of pharmacokinetic, metabolism, manufacturing and toxicological data wi ll be used in support of an IND and future clinical testing. The long term objective of this project is to make new oral drugs for the treatment of small pox. The expertise needed to succeed in this project will be provided by personnel at TSRL, Inc . in collaboration with Dr. John Drach, an expert in the area of antiviral drugs at the University of Michigan, and Dr. Charles Mckenna at the University of Southern California, who is well experienced at organic and medicinal chemistry of phosphorous cont aining compounds.

* information listed above is at the time of submission.

Agency Micro-sites


SBA logo

Department of Agriculture logo

Department of Commerce logo

Department of Defense logo

Department of Education logo

Department of Energy logo

Department of Health and Human Services logo

Department of Homeland Security logo

Department of Transportation logo

Enviromental Protection Agency logo

National Aeronautics and Space Administration logo

National Science Foundation logo
US Flag An Official Website of the United States Government