Nitric oxide and peroxynitrite are reactive, short-lived species that are important mediators of joint destruction in arthritis. Agents, which slow down or halt the development of joint destruction in arthritis may be useful for the experimental therapy of arthritis, when applied alone, or in combination with other anti-arthritic agents. The free radical related cellular cell injury is, at least in part, related to activation of a nuclear enzyme poly (ADP-ribose) synthetase (PARS). Furthermore, PARS activation promotes the expression of a variety of pro-inflammatory mediators relevant for the pathogenesis of arthritis. The applicants (Inotek Corp.) are involved in a project aimed at the development of therapeutically useful PARS inhibitors. The current application represents part of this effort. Moreover, the applicants have obtained preliminary data in vitro that PJ34, a novel, potent, water-soluble PARS inhibitor reduces free radical related injury in cultured cells. Furthermore, the applicants have obtained evidence that PJ34 has anti-inflammatory effects in various models of inflammation, including a model of shock induced by bacterial lipopolysaccharide, and in a model of collagen-induced arthritis. The applicants' long-term intention is to develop PJ34 or a lead compound from the PJ series of PARS inhibitors as an anti-arthritic drug.
The specific aim of the present proposal is to perform in vivo studies in order to test whether PJ34 can reverse the onset of arthritis. A further aim of the proposal is to optimize the administration of PJ34, in terms of dosage and time of administration. The results of the present application will permit application for Phase 2 SBIR funding to support: pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), investigational drug application to the FDA and a Phase 1 clinical trial.
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