4‐Substituted Indazoles as New Inhibitors of Neuronal Nitric Oxide Synthase.

Abstract

Pyrazole derivatives R 0180 4-Substituted Indazoles as New Inhibitors of Neuronal Nitric Oxide Synthase. -Halogenated indazoles such as (III) are obtained by diazotization of methylanilines (I), followed by cyclization of the resulting diazonium tetrafluoroborate salts (II) through promotion of potassium acetate and a crown ether. Position 4 of the new inhibitors seems to be as important as position 7 to confer inhibitory properties against NOS activity. The importance of position 4 is further demonstrated by the synthesis of the potent inhibitor 4-nitroindazole, which is obtained in the same manner from o-toluidine. The in vitro properties of the inhibitors are associated with an in vivo efficiency, as attested by potent antinociceptive effects following systemic administration. -(BOULOUARD, M.; SCHUMANN-BARD, P.; BUTT-GUEULLE, S.; LOHOU, E.; STIEBING, S.; COLLOT*, V.; RAULT, S.; Bioorg. Med. Chem. Lett. 17 (2007) 11, 3177-3180; Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.; Eng.) -H. Hoennerscheid 40-126

Development of an Efficient Pd-Catalyzed Coupling Process for Axitinib

“…9 In this approach, 6-iodoindazole (12) is prepared by commercial suppliers from 6-aminoindazole through a Sandmeyer reaction. 7 The Migita coupling of 12 with 10 is accomplished using Xantphos as a supporting ligand for Pd. 10 After formation of 13 is complete, 14 is formed in situ with addition of iodine and base.…”

“…The first C–C bond-forming step involves a Heck reaction between 5 and 2-vinylpyridine ( 6 ) to afford 7 . To set the stage for the final bond formation, the nitro group is reduced, and the amine undergoes a Sandmeyer reaction to provide 6-iodoindazole 9 . After coupling 9 with thiol 10 using Pd(dppf)Cl 2 as catalyst, THP-protected axitinib ( 11 ) is obtained.…”

L337H Mutant of Rat Neuronal Nitric Oxide Synthase Resembles Human Neuronal Nitric Oxide Synthase toward Inhibitors

“…It was not until 1995 that rat nNOS was successfully purified from overexpressed E. coli having full activity 12, 13. Because of the very high sequence identity with human nNOS and because of the reliable method to prepare it, rat nNOS has been widely used to screen selective nNOS inhibitors14, 15, 16, 17, 18 and for structural studies 14, 19, 20, 21…”

Unprecedented Rearrangement of 2-(2-Aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides to 2,3-Dihydro-1H-imidazo[1,2-b]indazoles

“…A review article by Cerecetto and colleagues 2 portrayed the diversity of biological activities exhibited by indazoles: recent advances in the chemistry of indazoles were reviewed by Schmidt and colleagues. 3 Since then, numerous new studies identified indazole-based compounds as potent agents with anti-inflammatory, anticancer, 4-6 antimicrobial, 7,8 antifungal, 9,10 and cytotoxic 11 activities.Indazoles were found to be potent inhibitors of nitric oxide synthetase, [12][13][14] factor Xa, 15 protein kinases, 16,17 tubulin, 18 reverse transcriptase, 19 vascular endothelial growth factor receptor, 20 and TRPV1. 21,22 Indazoles were active as male contraceptives 23,24 and 5-HT2C receptor agonists.…”

“…7.06 (ddd, J = 1.1, 6.6, 8.9 Hz, 1 H), 6.94-6.99 (m, 2 H), 6.72 (ddd, J = 0.9, 6.6, 8.5 Hz, 1 H), 4.38 (t, J = 8.4 Hz, 2 H), 4.00 (t, J = 8.4 Hz, 2 H), 3.79 (s, 3 H), 3.52-3.59 (m, 4 H). 13 C NMR (126 MHz, DMSO-d 6 ) δ 166.0, 161. 5, 152.5, 147.4, 128.9, 126.6, 125.6, 119.6, 117.1, 116.7, 113.4…”