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Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease

Award Number: U01AG068031
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease - ABSTRACT Alzheimer’s disease (AD) is the most common cause of dementia and one of the leading causes of death in the United States. AD is the only leading cause of death for which no disease-modifying therapy is currently available. Neuroinflammation plays a major role in AD pathogenesis. Epoxyeicosanoid signaling is a key integrator of cell-cell communication in the central nervous system (CNS), coordinating cellular responses across different cell types. Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites of cytochrome P450 epoxygenase that have potent anti-inflammatory activity. In our preliminary study, we demonstrated that pharmacological inhibition of sEH can attenuate neuroinflammation, enhance reduction of plaque pathology, and eventually reverse spatial learning and memory deficits in preclinical models of AD. Although some sEH inhibitors (sEHIs) have been reported, none of them are optimized for CNS applications. Blood brain barrier (BBB) is the main hurdle for CNS drug development. Taking advantage of high throughput virtual screening and medicinal chemistry optimization, we developed EHI-16 as a highly potent, orally available and brain permeable sEHI. Additionally, EHI-16 reduces LPS-induced neuroinflammation in both primary astrocytes and in vivo. In this project, we will further optimize EHI-16 to develop anti-inflammation therapy for AD treatment. To this end, we assembled a highly motivated and experienced team with complementary expertise. Dr. Wang is an expert on small molecule drug discovery and ADMET profiling. Dr. Zheng is a pioneer on AD pathophysiology and mouse modeling. Our expertise, highly promising preliminary data, and proven collaboration track-record will ensure the success of the proposed project. In Aim 1, we will develop potent, orally available, and CNS-penetrable sEHIs. In Aim 2, we will determine the pharmacokinetics-pharmacodynamics relationship of sEHIs and in vivo efficacy in attenuating neuroinflammation and improving cognitive impairment in AD mouse models. In Aim 3, we will determine the toxicity and PK profile of sEHIs in rats and dogs and perform IND-enabling studies. The successful accomplishment of this project will open a new avenue for treating and preventing AD and will advance our scientific knowledge of multiple mechanisms of AD.


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: 2027 ( Subtotal = -$1 )
2027	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	5	10/26/2026	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	001	5	3/27/2025	NON-COMPETING CONTINUATION	$0
2025	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	002	5	5/27/2025	NON-COMPETING CONTINUATION	$0
2025	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	5	3/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $804,669 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	001	5	5/29/2024	NON-COMPETING CONTINUATION	$804,669
2024	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	4	4/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $804,669

Issue Date FY: 2023 ( Subtotal = $1,258,021 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	002	4	6/21/2023	SUPPLEMENT FOR EXPANSION	$234,288
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	001	4	6/2/2023	NON-COMPETING CONTINUATION	$1,023,733
2023	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	3	10/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,258,021

Issue Date FY: 2022 ( Subtotal = $2,469,278 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	2	2/1/2022	SUPPLEMENT FOR EXPANSION	$249,942
2022	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	001	3	7/11/2022	NON-COMPETING CONTINUATION	$2,219,336
														Subtotal = $2,469,278

Issue Date FY: 2021 ( Subtotal = $2,089,925 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	2	5/26/2021	NON-COMPETING CONTINUATION	$2,089,925
														Subtotal = $2,089,925

Issue Date FY: 2020 ( Subtotal = $1,809,984 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	1	9/11/2020	NEW	$1,809,984
														Subtotal = $1,809,984

Grand Total All Awards = $8,431,876

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Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease

Award Number: U01AG068031

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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