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 = 36 lM] and 5 [1-(3-(2,3-dioxoindolin-1-yl)propyl)-1H-indazole-3-carboxamide, IC 50 = 6.8 lM]. 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.

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

“…Furthermore, having a sterically demanding t -Bu group at the indazole C-3 position ( 14 ) gave the N -1 substituted regioisomer 29 exclusively under both conditions A and B, respectively ( Table 2 , entry 3). Apart from the 1 H -indazole scaffold [ 36 – 37 ], the steric influence of adjacent substituent(s) on N -alkylation regioselectivity has previously been described for other nitrogen-containing heterocycles, such as pyrazole [ 38 ], purine, and related 1,3-azoles [ 39 ]. Although the N -alkylation of indazole 12, using conditions A (NaH in THF), proceeded with poor regioselectivity (ratio N -1 ( 25 ): N -2 ( 26 ) = 1:1.3), Bookser et al have obtained a similar regioselective outcome using a combination of NaHMDS and MeI instead of NaH and n -pentyl bromide ( Table 2 , entry 1), respectively [ 24 ].…”

Discovery and Structure–Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors

“…bIndazole lead compound (ILC) reported in ref (21) and clinical candidates ABT-888 and AZD-2281 were included as reference standards for comparative purposes.…”

“… a 28 1 and 28 2 represent the resolved enantiomers of the racemate 28 by chiral HPLC technique. b IC 50 values were determined by at least two independent experiments done in triplicate. c Indazole lead compound (ILC) reported in ref and clinical candidates ABT-888 and AZD-2281 were included as reference standards for comparative purposes. …”

“…Inhibitory activity of the synthesized PARP-1 inhibitors was determined using a commercially available 96-well assay kit (catalog no. 4677-096-K; universal colorimetric PARP assay kit from Trevigen, Inc., Gaithersburg, MD) according to the instructions provided by the manufacturer (with diminutive modifications) and our prior reports. , Briefly, the stock solutions of the various test compounds were made in dimethylsulfoxide (DMSO) and then serially diluted with distilled water to the required concentrations. In the beginning the strip wells were rehydrated by adding 50 μL of 1× PARP buffer into each well followed by incubation for 30 min.…”

“…Previously, we reported N-1 substituted indazole-3-carboxamide 21 and 2,8-disubstituted quinazolin-4(3 H )-one 22 derivatives as PARP-1 inhibitors. With the aims of structural novelty and improved potency of these scaffolds, we designed the previously unexplored pharmacophores 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2 H )-one-7-carboxamide (DHBF-3-one-7-carboxamide) that are targeted to the NAD + binding site of PARP-1.…”