Selective NR1/2BN-Methyl-d-aspartate Receptor Antagonists among Indole-2-carboxamides and Benzimidazole-2-carboxamides

Abstract

(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Similar to Zn 2ϩ binding to the ATD of GluN2A (see section VI.E), ifenprodil increases the potency of proton inhibition of NMDA receptors Mott et al, 1998). Rich pharmacology exists for this site, with nearly a dozen structural classes described, including oxamides (Barta-Szalai et al, 2004), 4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolines (Bü ttelmann et al, 2003), benzamidines (Claiborne et al, 2003), 5-substituted benzimidazoles (McCauley et al, 2004), indole-2-carboxamides (Borza et al, 2006(Borza et al, , 2007, benzyl cinnamamidines (Tamiz et al, 1999;Curtis et al, 2003), and other biaryl analogs (Tamiz et al, 1998;Wright et al, 2000;Tahirovic et al, 2008;Mosley et al, 2009). …”

An expedient general synthesis of pyrrolo[3,2-e]indazoles: domino Sonogashira/Cacchi coupling-heteroannulation reactions

“…The extant literature on the synthesis and bioactivity of pyrroloindazoles revealed that eight isomeric classes of pyrroloindazoles have so far been synthesised. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Of these, only the [2,3-g]-isomers [18][19][20][21][22][23][24][25][26][27] and the [3,2-e]-isomers 22,24,25 display various biological activities. Thus, the [2,3-g]-isomers 1-4 and the [3,2-e]-pyrroloindazole 5 were bioactive.…”

“…Thus, the [2,3-g]-isomers 1-4 and the [3,2-e]-pyrroloindazole 5 were bioactive. While 1 showed analgesic and antiinflammatory activity, 18 2 showed NMDA (N-methyl D-aspartate)-receptor antagonistic property with potential for the treatment of neuropathic pain, 22 3 and 4 displayed inhibition of sGC (soluble guanylate cyclase) with potential for treating hypertension 23 whereas 5 proved to be an antagonist of NMDA-receptor. Among these two classes of pyrroloindazoles, only the [2,3-g]-types have already been subjected to rather thorough synthetic investigations.…”

“…Among these two classes of pyrroloindazoles, only the [2,3-g]-types have already been subjected to rather thorough synthetic investigations. [18][19][20][21][22][23][24][25][26][27] But the [3,2-e]-types were synthesized only twice, neither of which was a general route.…”

“…The derived 4-benzylpiperidinylcarboxamide proved to be a good antagonist of NMDA-receptor. 22 In the second synthesis, 24,25 two substrates, viz. 6-H-and 6-bromo-4,5-indolynes, generated in situ, were separately treated with ethyl diazoacetate when a mixture of two isomeric pyrroloindazoles, viz.…”