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Lead Optimization of Peripheral CB1 Neutral Antagonists for Renal Diseases

Award Number: R41DK115303
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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Lead Optimization of Peripheral CB1 Neutral Antagonists for Renal Diseases - RESEARCH & RELATED – Unit 7 - PROJECT SUMMARY/ABSTRACT In response to PA-17-131, the aim of this Phase I STTR proposal is to optimize and develop peripherally acting ∼ cannabinoid 1 receptor (CB1R) neutral antagonists displaying favorable therapeutic profiles for treating diabetic nephropathy (DN). DN is a chronic diabetic kidney disease and affects 40% type 1 and type 2 diabetic patients. It is characterized by persistent albuminuria and abnormal renal function as represented by an abnormality in serum creatinine, calculated creatinine clearance, progressive decline in the glomerular filtration rate (GFR) and hypertension. DN can ultimately lead to end stage renal disease (ESRD) wherein a patient would require dialysis or a kidney transplant. The endocannabinoid system (ECS) has been implicated in the pathogenesis of DN, congruent with the observation that CB1R expression is dramatically increased in the kidney after the onset of DN. Notably, the pathophysiology of obesity-related renal dysfunction also contributes to DN. This is associated with hyperglycemia, hypertension, dyslipidemia and dietary protein intake. We have recently shown that blockade of CB1R is beneficial for treating DN wherein, AM6545, a peripherally acting CB1R neutral antagonist was shown to conserve renal structure and function. In a separate study, AM6545 was also shown to reduce renal fibrosis. Our group previously showed that AM6545 has positive metabolic effects. These data together indicate that peripheral CB1 blockade combined with neutral antagonism represents a novel mode of pharmacotherapy for treating DN and diabetes related complications including stabilizing metabolic parameters and treating renal fibrosis. AM6545 displays improved safety profiles when compared to known brain penetrant CB1R inverse agonists and is the only validated pharmacological tool available in this class. AM6545 can be used as an excellent prototype for the development of improved druggable candidates for treating DN. Based on our preliminary studies, we have now identified an early lead which displays the beneficial properties as AM6545. In this STTR proposal, aim 1 and aim 2 will focus on the optimization of our early lead and to develop selective high affinity CB1 neutral antagonists displaying improved aqueous solubilities. Aim 3 will comprise testing of compounds in vivo so as to quantify them in brain and plasma and identify non-brain penetrants displaying improved oral bioavailabilities. Subsequently, we will focus on testing the optimized leads in validated pre-clinical rodent models of DN that are considered perfect translational models to humans. These studies will be planned based on a collaboration with the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School. If successful, Phase II of this grant will focus on identifying a candidate and 2-3 backups and then advancing the lead candidate towards IND-enabling studies while partnering with a major biotechnology company.


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: 2022 ( Subtotal = $0 )
2022	2019	MAKSCIENTIFIC, LLC	151 S BEDFORD ST STE 104-B	BURLINGTON	MA	01803	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/16/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	MAKSCIENTIFIC LLC	151 SOUTH BEDFORD SREET, SUITE 104-B	BURLINGTON	MA	01803	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/24/2020	NEW	$0
2020	2019	MAKSCIENTIFIC LLC	151 SOUTH BEDFORD SREET, SUITE 104-B	BURLINGTON	MA	01803	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/22/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $224,999 )
2019	2019	MAKSCIENTIFIC LLC	151 SOUTH BEDFORD SREET, SUITE 104-B	BURLINGTON	MA	01803	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/13/2019	NEW	$224,999
2019	2019	MAKSCIENTIFIC LLC	151 SOUTH BEDFORD SREET, SUITE 104-B	BURLINGTON	MA	01803	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/13/2019	NEW	$0
														Subtotal = $224,999

Grand Total All Awards = $224,999

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Lead Optimization of Peripheral CB1 Neutral Antagonists for Renal Diseases

Award Number: R41DK115303

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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