title: Design and synthesis of N-substituted indazole-3-carboxamides as poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors(†).
abstract: 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 1H-indazole-3-carboxamide 2, by introducing a three carbon linker between 1H-indazole-3-carboxamide and different heterocycles, and led to compounds 4 [1-(3-(piperidine-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) =36μm] and 5 [1-(3-(2,3-dioxoindolin-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) = 6.8μm]. 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA.
authors.forename: Maulik R
authors.initials: MR
authors.lastname: Patel
authors.forename: Kashyap G
authors.initials: KG
authors.lastname: Pandya
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Lau-Cam
authors.forename: Satyakam
authors.initials: S
authors.lastname: Singh
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pino
authors.forename: Blase
authors.initials: B
authors.lastname: Billack
authors.forename: Kurt
authors.initials: K
authors.lastname: Degenhardt
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology; D015195:Drug Design; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D007004:Hypoglycemic Agents; D007191:Indazoles; D007328:Insulin; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases