Blockade of A2B adenosine receptors (A2BARs) increases insulin sensitivity in insulin resistant obese Zucker rats by an effect on skeletal muscle. We have synthesized and characterized the first potent and selective antagonists of A2B receptors. The goal of this phase I SBIR proposal is to develop improved A2BAR antagonists as new candidate drugs for the treatment of insulin resistance.
Aim 1 is to synthesize additional A2BAR structures that have improved aqueous solubility but that maintain high potency and selectivity for human and rat A2BARs.
Aim 2 is to determine pharmacokinetics of candidate compounds in rats. Preliminary data indicate that MRS1754, a prototype selective A2B antagonist, and BWA1433, a nonselective Al and A2B antagonist, are able to improve insulin sensitivity in insulin resistant Zuker rats. These findings cannot be replicated using the A1AR-selective antagonist, cyclopentyl-1,3-dipropyl-xanthine (CPX).
Aims 3 and 4 of this proposal are designed to prove that A2B adenosine receptor blockade improves insulin sensitivity in rat models of insulin resistance. There is a great need for improved therapies to treat type II diabetes and insulin resistance that commonly accompany obesity.
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