Non-Lipogenic ABCA1 Inducers for Type 2 Diabetes and Alzheimer's Disease

Increased expression of the ATP-binding cassette family member A1 (ABCA1) protein elicits numerous therapeutic effects against type 2 diabetes, Alzheimer’s disease, and other related conditions in preclinical models. However, side effects such as increased lipogenesis and neutropenia have precluded translation of ABCA1-inducing compounds to the clinic. This project utilized a unique phenotypic strategy to develop selective, non-lipogenic ABCA1 inducers as multifunctional therapeutic candidates for Alzheimer’s disease and type 2 diabetes. The approach consisted of chemical synthesis to optimize a screening hit into lead candidates with enhanced potency and efficacy, followed by testing in an array of cell and animal models. Hit-to-lead optimization of the initial screening hit F420 yielded two key lead compounds, CL2-57 and CL3-3. Both lead compounds selectively enhanced expression of ABCA1 over genes promoting hepatic lipogenesis. This selectivity stemmed from combined agonist and antagonist effects at multiple nuclear receptor isoforms, which represented a novel mechanism of action. Additionally, compound CL3-3 displayed a stronger combination of potency for ABCA1 induction and selectivity against lipogenic gene induction than the best previously reported agonists. These two non-lipogenic ABCA1 inducers also enhanced cholesterol efflux and blunted pro-inflammatory signaling in cell-based assays. After in vitro testing, the lead compounds were evaluated for safety and efficacy in mouse models. Both ABCA1 inducers maintained functional selectivity in vivo, enhancing ABCA1 expression and modifying disease phenotypes while avoiding unwanted effects, such as increased triglycerides. Major efficacy readouts included phenotypic, biochemical, and metabolomic analysis of a high-fat diet mouse model. Oral treatment with CL2-57 enhanced glucose homeostasis, reduced adiposity, attenuated inflammation, and reversed metabolic perturbations in mice fed the high-fat diet. Oral treatment with CL3-3 also induced cholesterol transport genes in the brain and periphery, while triglyceride increases were avoided. Testing for effects of CL3-3 on Alzheimer’s-related pathology in additional mouse models is ongoing, but these compounds are promising leads for further development as Alzheimer’s disease and type 2 diabetes therapeutics.