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.
RESEARCH & RELATED - Unit 8 - PROJECT NARRATIVE The goal of this Phase I STTR proposal is to develop peripherally restricted CB1R neutral antagonists for treating diabetic nephropathy (DN). There is no specific FDA-approved medication that targets DN, prevents end-stage renal disease (ESRD) or renal fibrosis, while displaying positive metabolic effects. In this regard, an agent that can stop or delay the progression of DN and prevent overt DN, offers a major therapeutic advantage. The proposed research aims towards developing a treatment for DN using a new and novel mode of pharmacotherapy and satisfies a therapeutic need that is relevant to NIDDK's mission.
