Sunday, May 11, 2025
5/11/2025
Lead identification and pre-clinical studies on allosteric inhibitors of coagulation factor XIa - Anticoagulants are the mainstay in the treatment of thrombotic diseases, such as heart attack and stroke, and may also be used in other diseases such as cancer and COVID-19. Although several anticoagulants including heparins, warfarin, and direct oral anticoagulants (DOACs) are used in the clinic, each agent suffers from major and minor bleeding adverse effects. As of now, a safe anticoagulant that inhibits coagulation without bleeding risk has not been developed as yet. Under the NHLBI's R01 mechanism, we earlier discovered that the heparin-binding exosite 2 of human factor XIa (hFXIa) is remarkably different from other homologous coagulation proteases (e.g., hFIIa, hFXa and others). We developed a novel design strategy that relies on anionic sulfates and aromatic rings to effect highly selective recognition of hFXIa's exosite 2 resulting in inhibition of enzyme activity. We developed a highly promising allosteric inhibitor, named sulfated D-chiro-inositol (SCI), which was synthesized in four steps, displayed >100-fold selectivity for hFXIa; bound plasma FXIa in exosite 2 with an affinity of 20–60 nM even when the enzyme's active site was covalently blocked; and inhibited in vivo arterial and venous thrombosis in the rat at 250 µg per animal (~1 mg/kg) without enhancing tail bleeding. SCI was tolerated at doses as high as 25 mg/rat suggesting a therapeutic window of ~100. SCI is a highly promising anticoagulant; yet its pharmacokinetics is not the best. Using cues from heparin-based drugs, we hypothesize that optimizing the number and position of sulfate groups on the D-chiro inositol scaffold, while also screening its various stereoisomers would improve hFXIa affinity, inhibition potency, PK, pharmacodynamics (PD), and chemistry, manufacturing and controls (CMC) properties before embarking on IND-enabling studies. The current proposal focuses on studying a library of 20 rationally designed SCI analogs with the goal of identifying at least one LEAD AGENT for advanced stage pre-clinical development. The specific aims are 1) synthesis, anticoagulation efficacy, and bleeding of 20 putative factor XIa inhibitors based on the SCI structure; 2) in vivo antithrombotic efficacy, DMPK, in vitro and in vivo toxicity of inhibitors; and 3) scaled-up non-GMP synthesis, CMC, dose escalation efficacy, and PD studies to identify one or two lead molecules. SCI has been claimed in a US patent (#9,758,459 B2 titled `Allosteric modulators of factor XIa as anticoagulant agents') with the PI as one of the inventors. Quantitative milestones with regard to synthesis, in vitro & in vivo efficacy, in vitro and in vivo toxicity will be used to guide the transition from the R61 to R33 Phase. Alternatively, the best 1 (or 2) analogs of SCI would be identified as the most promising agent for further IND-enabling studies starting from the 20 designed SCI analogs.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).