Metal Coordination-Based Inhibitors of Adenylyl Cyclase:  Novel Potent P-Site Antagonists

The adenylyl cyclases (ACs) are a family of intracellular enzymes associated with signal transduction by virtue of their ability to convert ATP to cAMP. The catalytic mechanism of this transformation proceeds through initial binding of ATP to the so-called purine binding site (P-site) of the enzyme followed by metal-mediated cyclization with loss of pyrophosphate. Crystallographic analysis of ACs with known inhibitors reveals the presence of two metals in the active site. Presently, nine isoforms of adenylyl cyclase are known, and unique isoform combinations are expressed in a tissue-specific manner. The development of isoform-specific inhibitors of adenylyl cyclase may prove to be a useful strategy toward the design of unique signal transduction inhibitors. To develop novel AC inhibitors, we have chosen an approach to inhibitor design utilizing an adenine ring system joined to a metal-coordinating hydroxamic acid via various linkers. Previous work in our group has validated this approach and identified novel inhibitors that possess an adenine ring joined to a metal-coordinating hydroxamic acid through flexible acyclic linkers (Levy, D. E., et al. Bioorg. Med. Chem. Lett. 2002, 12, 3085−3088). Subsequent studies have focused on the introduction of conformational restrictions into the tether of the inhibitors with the goal of increasing potency (Levy, D. E., et al. Bioorg. Med. Chem. Lett. 2002, 12, 3089−3092). Building upon the favorable spatial positioning of the adenine and hydroxamate groups coupled with potentially favorable entropic factors, the unit joining the carbocycle to the hydroxamate was explored further and a stereochemical-based SAR was elucidated, leading to a new series of highly potent AC inhibitors.