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Principal Investigator: Umesh Ramanlal Desai
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
Fiscal Year: 2024
Award: $489,038
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Activated Blood Coagulation Factor XI><Activated Factor XI><Active Sites><Adverse effects><Affinity><Angina at Rest><Animals><Anticoagulant Agents><Anticoagulant Chemotherapy><Anticoagulant Drugs><Anticoagulant therapy><Anticoagulants><Anticoagulation><Antithrombotic Agents><Antithrombotic Drugs><Apoplexy><Area><Binding><Biological><Biotech><Biotechnology><Bleeding><Blood Plasma><Brain Vascular Accident><COVID-19><CV-19><Cancers><Cardiac infarction><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemistry><Chiro-Inositol><Clinic><Clinical><Clinical Research><Clinical Study><Clotting><Coagulation><Coagulation Factor XIa><Coagulation Process><Common Rat Strains><Contact Activation Product><Coronavirus Infectious Disease 2019><Cues><Disease><Disorder><Dose><Drug Costs><Drug Interactions><Drug Kinetics><Drug usage><Drugs><Elements><Enoxaparin><Enzyme Gene><Enzyme Inhibition><Enzymes><Esteroproteases><Factor XIa><Fibrinolytic Agents><Fibrinolytic Drugs><Goals><Health><Hemorrhage><Heparin><Heparin Binding><Heparinic Acid><Human><In Vitro><Incubators><Inositol><Institution><Lead><Leadership><Legal patent><Libraries><Location><Lovenox><Malignant Neoplasms><Malignant Tumor><Measures><Medication><Mesoinositol><Minor><Modern Man><Molecular Interaction><Myocardial Infarct><Myocardial Infarction><NHLBI><Names><National Heart, Lung, and Blood Institute><New Agents><Oral><Out-patients><Outpatients><PK/PD><Patents><Pathway interactions><Pb element><Peptidases><Peptide Hydrolases><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phase><Phlebothrombosis><Plasma><Plasma Serum><Population Characteristics><Position><Positioning Attribute><Preinfarction Angina><Preparation><Property><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><R-Series Research Projects><R01 Mechanism><R01 Program><Rat><Rats Mammals><Rattus><Renal clearance function><Research Grants><Research Project Grants><Research Projects><Reticuloendothelial System, Serum, Plasma><Risk><Role><Self Administered><Self Administration><Stereoisomer><Stroke><Structure><Sulfate><Tail><Technology><Therapeutic><Thrombolytic Agents><Thrombolytic Drugs><Thrombosis><Toxic effect><Toxicities><Unstable angina><Venous Thrombosis><Warfarin><analog><antithrombotic medication><antithrombotics><biologic><blood loss><blood thinner><brain attack><cardiac infarct><cerebral vascular accident><cerebrovascular accident><coronary attack><coronary infarct><coronary infarction><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cost><design><designing><drug development><drug metabolism><drug standard><drug use><drug/agent><enzyme activity><experience><heart attack><heart infarct><heart infarction><heavy metal Pb><heavy metal lead><heparin bound><improved><in vivo><inhibitor><interest><malignancy><manufacture><name><named><naming><neoplasm/cancer><novel><pathway><pharmacokinetics and pharmacodynamics><pre-clinical development><pre-clinical study><preclinical development><preclinical study><preparations><rational design><renal clearance><scaffold><scaffolding><scale up><screening><screenings><small molecule><social role><stroked><strokes><thrombopoiesis inhibitor><thrombotic><thrombotic disease><thrombotic disorder>