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Inhibitors of the Intrinsic Pathway of Coagulation as New Anticoagulants

Award Number: SC3GM131986
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 04/16/2023

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Inhibitors of the Intrinsic Pathway of Coagulation as New Anticoagulants - SUMMARY Anticoagulants are clinically used to prevent and/or treat thrombotic diseases. Yet, all current anticoagulants are associated with a significant risk of internal bleeding which subsequently limits their effective use in various patient populations. The long-term goal of research in this area is to introduce effective anticoagulants that do not cause bleeding complications so as to be safely used for a wider range of thrombotic patients. Thus, this project aims at developing effective and safe anticoagulants by targeting procoagulant proteases in the intrinsic pathway of coagulation, particularly factor XIa (FXIa) and/or factor XIIa (FXIIa). Clinically used anticoagulants inhibit directly or indirectly thrombin and/or factor Xa of the common pathway of coagulation. This is the reason why they are clinically effective, but it is also the reason why they cause bleeding. The central hypothesis is that inhibiting human FXIa or FXIIa of the intrinsic pathway will result in effective protection against both arterial and venous thromboses without causing bleeding. Inhibitors of FXIa or FXIIa will primarily prevent thrombosis and will leave the hemostatic process essentially intact. In preliminary studies, I identified a sulfonated peptidomimetic that allosterically inhibits FXIa with moderate potency and significant selectivity over thrombin and factor Xa. I also identified a benzamide that orthosterically inhibits FXIIa with high potency and significant selectivity over a panel of related proteases. Not only that but each of these two inhibitors also dose-dependently prolongs the clotting time of human plasma when coagulation is initiated through the intrinsic pathway which further supports their specificity of function. Therefore, the two inhibitors of FXIa and FXIIa exhibit very promising profiles as effective and potentially safe anticoagulants, yet their pharmaceutical and pharmacological properties require further improvement. Thus, I specifically aim to; 1) chemically synthesize an advanced library of sulfonated allosteric inhibitors of FXIa and evaluate their biochemical and biological potential as anticoagulants and 2) chemically synthesize an advanced library of benzamide-based orthosteric inhibitors of FXIIa and evaluate their biochemical and biological potential as anticoagulants. The proposal is innovative because i) it puts forward a novel approach to overcome the limitations of current thrombosis treatment; ii) it exploits a highly integrated, multidisciplinary approach involving synthetic medicinal chemistry, enzyme kinetics, molecular modeling, and testing in human plasmas to investigate the specific aims; and iii) it introduces new technologies with proprietary structural and mechanistic aspects. The project is also significant because it will identify 2-4 potent and selective inhibitors of the intrinsic coagulation pathway for future evaluation in animal models of thrombosis and bleeding.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$114,604 )
2024	2022	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	001	4	1/10/2024	NON-COMPETING CONTINUATION	-$106,500
2024	2021	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	3	1/10/2024	NON-COMPETING CONTINUATION	-$8,104
														Subtotal = -$114,604

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	4	9/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $106,500 )
2022	2022	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	4	3/25/2022	NON-COMPETING CONTINUATION	$95,850
2022	2022	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	001	4	6/27/2022	NON-COMPETING CONTINUATION	$10,650
														Subtotal = $106,500

Issue Date FY: 2021 ( Subtotal = $106,500 )
2021	2021	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	3	3/24/2021	NON-COMPETING CONTINUATION	$106,500
														Subtotal = $106,500

Issue Date FY: 2020 ( Subtotal = $106,500 )
2020	2020	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	2	3/31/2020	NON-COMPETING CONTINUATION	$106,500
														Subtotal = $106,500

Issue Date FY: 2019 ( Subtotal = $106,500 )
2019	2019	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	1	3/20/2019	NEW	$106,500
														Subtotal = $106,500

Grand Total All Awards = $311,396

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Inhibitors of the Intrinsic Pathway of Coagulation as New Anticoagulants

Award Number: SC3GM131986

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 04/16/2023

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