Design and Synthesis of N ‐Substituted Indazole‐3‐Carboxamides as Poly(ADP‐ribose)polymerase‐1 (PARP‐1) Inhibitors †

A group of novel N ‐1‐substituted indazole‐3‐carboxamide derivatives were synthesized and evaluated as inhibitors of poly(ADP‐ribose)polymerase‐1 (PARP‐1). A structure‐based design strategy was applied to a weakly active unsubstituted 1 H ‐indazole‐3‐carboxamide 2 , by introducing a three carbon linker between 1 H ‐indazole‐3‐carboxamide and different heterocycles, and led to compounds 4 [1‐(3‐(piperidine‐1‐yl)propyl)‐1 H ‐indazole‐3‐carboxamide, IC 50  = 36 μ m ] and 5 [1‐(3‐(2,3‐dioxoindolin‐1‐yl)propyl)‐1 H ‐indazole‐3‐carboxamide, IC 50  = 6.8 μ m ]. Compound 5 was evaluated in rats for its protective action against diabetes induced by a treatment with streptozotocin, a known diabetogenic agent. In addition to preserving the ability of the pancreas to secrete insulin, compound 5 was also able to attenuate the ensuing hyperglycemic response to a significant extent.