Structure−Activity Relationships of Potent, Selective Inhibitors of Neuronal Nitric Oxide Synthase Based on the 6-Phenyl-2-aminopyridine Structure

Abstract

The synthesis and structure-activity relationships of a series of 6-phenyl-2-aminopyridines that potently and selectively inhibit the neuronal isoform of nitric oxide synthase (nNOS) are described. Compound 14bi from this series exhibits potent in vivo activity in harmaline-induced cGMP formation in rat cerebellum, a functional model of nNOS inhibition, and in the PCP-induced hypermotility model in the rat. These results suggest that 14bi may be a useful reagent for evaluating potential therapeutic applications of nNOS inhibitors in the central nervous system.

Nanocrystalline Titania‐Supported Palladium(0) Nanoparticles for Suzuki–Miyaura Cross‐Coupling of Aryl and Heteroaryl Halides

“…[30] A useful synthetic tool for the modification of such compounds is the Suzuki-Miyaura coupling, [31] which has been applied for the preparation of arylpyridines, [32] bipyridines, [33] arylpyrimidines, [34] and the synthesis of nucleosides. [35] Unfortunately, nitrogen-containing heterocycles are difficult substrates for Suzuki-Miyaura cross-coupling reactions.…”

Synthesis and evaluation of pyrido[1,2-a]pyrimidines as inhibitors of nitric oxide synthases

“…Using phenyl, naphthyl, biphenyl, and benzyloxyphenyl substituted enone Mannich bases 4-6 for the ring closure reaction, the corresponding 3-aroylpyrido[1,2-a]pyrimidine derivatives 8-37 were obtained in moderate (30%) to good (70%) yields from commercially available aryl methyl ketones following simple procedures. Twenty six 3-benzoyl derivatives 8-22, five pyrido[1,2-a]pyrimidines 23-28 bearing a benzyloxybenzoyl substituent in position 3, nine naphthoyl (28)(29)(30) and ten biphenyloyl substituted heterocycles (31)(32)(33)(34)(35)(36)(37) were synthesized and evaluated as inhibitors of the three purified NOS isoforms.…”

“…Potent non-amino acid inhibitors with iso-thiourea and amidine functions have been reported [27][28][29][30][31][32][33][34][35]. 2-Aminopyridines have been described as NOS inhibitors, and selective nNOS inhibitors containing this scaffold were recently reported [36,37]. However, 2-amino-4-methylpyridine derivatives, which are reported to be highly potent inhibitors of all three isoforms, can exhibit high toxicity and should not be suitable for further development [36].…”

Thermoregulated ligand–palladium‐catalyzed Suzuki reaction in water

“…However, this type of catalyst was less active towards 3-pyridyl wileyonlinelibrary.com/journal/aoc bromides. As aryl-substituted pyridines are the most common N-heteroaryl units in pharmaceutically active compounds, [23] we further investigated the Suzuki reaction of 3-pyridyl bromides with arylboronic acids. Under the reaction conditions used, the Suzuki reaction of 3-bromopyridine with arylboronic acids containing either electron-donating or electron-withdrawing groups afforded excellent yields (Table 5, entries 1-3).…”