SMALL MOLECULE ANTAGONISTS OF PF FOR THE TREATMENT AND PREVENTION OF HIT

DESCRIPTION provided by applicant We have discovered the first ever inhibitors of PF a platelet protein central to the pathophysiology of heparin induced thrombocytopenia HIT Heparin is a naturally occurring anticoagulant that prevents the formation of clots and extension of existing clots within the vasculature and major medical applications of heparin include dialysis cardiac catheterization and cardiopulmonary bypass surgery Heparin therapy is usually safe and effective however some patients develop HIT as a serious complication caused by an immunological reaction that targets platelets leading to a low platelet count thrombocytopenia HIT increases the risk of blood clots forming within blood vessels and blocking the flow of blood thrombosis referred to as HITT when thrombosis occurs HITT develops in approximately of patients treated with heparin for days Affected individuals have a risk of developing new thromboembolic events a mortality rate and an additional of patients require amputations or suffer other major morbidity Current treatment for HIT relies on elimination of heparin exposure from patients with suspected HIT and administration of direct thrombin inhibitors which carry a significant risk of bleeding Despite the removal of heparin from these patients they remain at significant risk for thrombosis and death We have discovered a novel approach to the treatment of HIT via the destabilization of the functionally active PF tetramers to inactive monomers and dimers The tetrameric form of PF binds to heparin to form Ultra large Complexes ULC We have recently reported on the identification and characterization of PF antagonists PF As that disrupt PF tetramerization which is a prerequisite for ULC formation and inhibit the formation of ULCs In this grant proposal further we optimize our current series of PF tetramerization inhibitors lead compound FC by designing and preparing new analogs that have improved potency and similar or better ADMET and drug like properties Using the combined expertise of Fox Chase Chemical Diversity Center Inc in medicinal chemistry and drug discovery and the Sachais Laboratory at the New York Blood Center in HIT based approaches we anticipate this Phase II project to result one or more PF lead antagonists suitable for IND safety evaluation and ultimate evaluation in a clinical setting under IV administration The first aim is lead optimization synthetic and medicinal chemistry Aim is the evaluation of analogs in in vitro assays for targeted activities inhibition of PF tetramerization ULC inhibition and inhibition of cellular activation Aim is for the evaluation of analogs for acceptable ADMET drug values including metabolic stability microsomes aqueous solubility lipophilicity CypP inhibition isozymes most likely to cause exposure variability and drug drug interactions and in vivo pharmacokinetics in mice after IV administration Safety assays on selected top compounds include in vivo tolerability MTD in mice hERG and Ames evaluation Aim involves evaluation of select analogs in the mouse HIT model PUBLIC HEALTH RELEVANCE Heparin induced thrombocytopenia HIT is a serious complication of heparin therapy placing patients at increased risk for thrombosis clotting and death We have identified small molecule hits that block the functions of a protein called PF a platelet protein central to the pathophysiology of HIT by the destabilizing PF tetramers so that inactive monomers and dimers predominate In vitro and in vivo data for these PF antagonists in models predictive of activity for HIT support the merits of this approach which we anticipate will eventually result in the discovery of first in class therapeutic agents for the treatment of HT