TY - JOUR
T1 - Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine- based selective inhibitors of human neuronal nitric oxide synthase (nNOS)
AU - Annedi, Subhash C.
AU - Ramnauth, Jailall
AU - Cossette, Michele
AU - Maddaford, Shawn P.
AU - Dove, Peter
AU - Rakhit, Suman
AU - Andrews, John S.
AU - Porreca, Frank
N1 - Funding Information:
We are grateful to NoAb BioDiscoveries Inc. (Mississauga, ON, Canada), Asinex Ltd (Moscow, Russia) for performing the human NOS inhibition assays and Cerep (France) for hERG K + channel assay and broad screen profile. We thank the Natural Sciences and Engineering Research Council (NSERC) of Canada for providing an undergraduate student research award (USRA) for M.C.
PY - 2012/4/1
Y1 - 2012/4/1
N2 - A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K + channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels).
AB - A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K + channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels).
KW - 2,3,4,5-Tetrahydro-1H-benzo[b]azepine derivatives
KW - Neuropathic pain
KW - Nitric oxide
KW - Nitric oxide synthase
KW - Selective neuronal nitric oxide synthase inhibitors
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U2 - 10.1016/j.bmcl.2012.02.004
DO - 10.1016/j.bmcl.2012.02.004
M3 - Article
C2 - 22370270
AN - SCOPUS:84858702117
SN - 0960-894X
VL - 22
SP - 2510
EP - 2513
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 7
ER -