A CB1 Antagonist for Treatment of Kidney Disease

OTHER PROJECT INFORMATION – Unit 7 - SUMMARY/ABSTRACT Chronic kidney disease (CKD) is a major public health issue affecting ~700 million worldwide, including 15% in the US. The most common form is diabetic kidney disease (DKD), affecting 40% of diabetics and occurring 3.5 times more frequently among diabetics than non-diabetics. Clinical symptoms include progressive albuminuria, decline in glomerular filtration rate and glomerular hyperfiltration and sclerosis, hypertrophy, podocyte injury and depletion on a cellular level, eventually culminating in end stage kidney disease (ESKD). In diabetic patients, CB1 receptor is upregulated in glomerular podocytes and involved in development of renal fibrosis. Thus, blocking the CB1 receptor represents a viable strategy in combatting DKD. We have demonstrated that our peripherally acting CB1 neutral antagonist, AM6545, has a positive effect on metabolic and renal function, improving hyperglycemia, dyslipidemia, and fatty liver, and mitigating development of metabolic syndrome. In rodent diabetes models, AM6545 slowed albuminuria, nephrin loss, inflammation, and fibrosis. The combination of AM6545 with perindopril (ACE inhibitor) or AM1241 (CB2 agonist) was even shown to reverse clinical markers of DKD. Further modifications on AM6545 led to the discovery of AM6588 with improved affinity for CB1 (Ki = 0.9 nM), excellent metabolic stability profile in human microsome and hepatocytes (t1/2 > 60 min). However, its aqueous solubility (28 µg/mL) and bioavailability (F ~ 2%) were still suboptimal. Hence, this proposal aims to develop novel peripherally acting CB1 neutral antagonists, based on AM6588, with improved pharmacokinetic parameters. In Phase I, Aim 1, we will design and synthesize analogs which possess the aromatic alkynyl heterocycle core, aiming to increase potency and CB1 selectivity, enhance oral bioavailability, metabolic stability, and reduce brain permeability. Analogs will be evaluated for their ADME profiles. In Aim 2, one advanced lead will be selected and tested for its efficacy in the ZSF-1 diabetic rat model, a validated and robust model for DKD. In Phase II, Aim 3, the advanced lead will undergo a series of IND- enabling studies (CMC development and formulation) to prepare for IND filing. An additional diabetes animal model (db/db AAV-renin uni-nephrectomized model) will be used to validate the efficacy of lead. In Aim 4, further IND preparation will be completed by partnering with experienced regulatory and business consultants. Completion of this project will result in one advanced lead candidate ready for further IND enabling studies and eventual development of a novel therapeutic mode for DKD.