Diabetes is the most prevalent endocrine disorder affecting nearly 29.1 million patients in the US in 2013, approximately 9.3% of the population, according to American Diabetes Asssociation (ADA) estimates. Approximately 95% of these patients have type 2 diabetes, which is characterized by an inadequate glucose stimulated insulin response and insulin resistance in tissues, or both. Diabetes is also associated with an increased risk other serious health conditions including heart disease, stroke, hypertension, kidney disease, retinal degeneration, neurological disease, and hyperlipidemia. Diabetes is the seventh leading cause of death in the US. In addition to insulin replacement, diabetes is treated with drugs that lower insulin resistance, increase insulin secretion, or alter hepatic gluconeogenesis. However none of these approaches address the progressive decrease in beta-cell function that often leads to type-2 diabetics becoming insulin dependent. A drug that increases beta-cell number and function would be a very important advance in the treatment of both Type -1 (“Juvenile”) and type-2 diabetes.
Memapsin 1 / BACE-2
BACE-2 has recently been identified as a key regulatory enzyme effecting pancreatic Beta-cell number and function (Esterhazy 2011). BACE-2 cleaves the ectodomain of Tmem-27 (or collectrin), a transmembrane protein that controls Beta-cell proliferation and glucose stimulated insulin release. Down regulation of Tmem-27 by genetic modification of its transcription factor (Tcf1) causes a form of diabetes. Cleaving the ectodomain inactivates Tmem-27, which is associated with reduced Beta-cell mass and decreased insulin secretion while overexpression of Tmem-27 increases Beta-cell mass and glucose stimulated insulin secretion (Figure 1). Importantly inhibition of BACE-2 with small molecule inhibitors increases Beta-cell mass and glucose stimulated insulin secretion, and lowers blood glucose levels in diabetic (ob/ob) mice.
Figure 1. Therapeutic concept of memapsin 1 inhibition for treating Type 2 diabetes. A. The abundance of Tmem27 regulates the function and mass of pancreatic beta-cells. Tmem27 is reduced by memapsin 1 cutting. B. Memapsin 1 cutting of Tmem27 reduces the number of beta cells and resulted in less insulin production. C. A memapsin 1 inhibitor suppresses Tmem27 cutting, increases beta cell number and function, increases insulin production, and lowers blood glucose and HbA1c.
BACE-2 Inhibitors for Diabetes
JORTAN has an available library of patented and patent-pending small molecule compounds characterized for their BACE-2 and BACE-1 selectivity, including compounds with low nanomolar potency and high selectivity for BACE-2 over BACE-1 (Figures 2 & 3). Jortan’s small molecules are selective low nanomolar inhibitors of BACE-2 and have been shown to lower blood glucose levels in ob/ob mice by up to 20%. A prototype molecule in the literature has been shown to increase beta cell mass. Imaging studies are currently underway to determine in vivo beta cell proliferation. JORTAN is uniquely positioned to quickly identify an IND candidate that will increase Beta-cell number and function as a prospective treatment for Type 1 and Type 2 diabetes.
Figure 2. An energy-minimized model of a prototype M1 inhibitor (blue) in memapsin 1 (blue) active site. Dotted line represents hydrogen bond.
Figure 3. An energy-minimized model of a prototype M1 inhibitor (green) in memapsin 1 active site. Dotted line represents hydrogen bond.