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Design and Synthesis of N ‐Substituted Indazole‐3‐Carboxamides as Poly(ADP‐ribose)polymerase‐1 (PARP‐1) Inhibitors †
Author(s) -
Patel Maulik R.,
Pandya Kashyap G.,
LauCam Cesar A.,
Singh Satyakam,
Pino Maria A.,
Billack Blase,
Degenhardt Kurt,
Talele Tanaji T.
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01302.x
Subject(s) - indazole , carboxamide , poly adp ribose polymerase , chemistry , polymerase , stereochemistry , biochemistry , enzyme
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.