Challenge of creating single-agents for the treatment of type 1 and 2 diabetes by targeting retinoid X receptor

It might be seen as reckless to challenge to create single-agents for the treatment of both type 1 diabetes caused by the destruction of the Langerhans β cells in pancreas by excessive autoimmunity, and type 2 diabetes caused by the obesity. However, we hypothesized that retinoid X receptor (RXR) agonists, which are researched for the treatment of type 2 diabetes, will also be useful like metformin, which shows insulin-sparing effect in type 1 diabetes. This is because PPARg /RXR is known to be a target of thiazolidinediones (TZDs), which are used for the treatment of insulin resistance, LXR /RXR is reported to be involved in glucose/lipid metabolism, and these heterodimers can be activated by RXR agonists alone (permissive mechanism). However, repeated administration of RXR agonists can elevate blood triglyceride and induce hypothyroidism. In this study, we performed systematic conversion of the alkoxy side chain of 5a (6-[ethyl-(3- isopropoxy-4-isopropylphenyl)amino] nicotinic acid: NEt-3IP) and evaluated the RXR-, PPAR/RXR- and LXR/ RXR-agonist activities of the products. The cyclopropylmethoxy analog (5c) showed similar RXR- and LXR/RXRagonistic activities to the benzyloxy analog (5i) and n-propoxy analog (5k), but exhibited more potent PPAR/RXRagonistic activity than 5i or 5k. DiŠerential modulation of RXR heterodimer-activating ability by conversion of the alkoxy group located in the lipophilic domain of the RXR-agonist common structure is expected to be a useful approach in the design of new RXR agonists for the treatment of hyperlipidemia.