- Hedgehog signal pathway inhibitor
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The invention provides a Hedgehog signal pathway inhibitor as well as stereoisomers, tautomers, hydrates, solvates or pharmaceutically acceptable salts thereof, and the structural formula of the inhibitor is as shown in a formula (I). The invention further provides a preparation method and application of a compound. The compound provided by the invention is novel in structure; a signal transduction pathway adjusted by Hedgehog protein, Ptch, Gli and/or Smo can be adjusted through the compound of the formula I.
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Paragraph 0103; 0109
(2017/06/20)
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- Subtype-selective Nav1.8 sodium channel blockers: Identification of potent, orally active nicotinamide derivatives
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A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Nav1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
- Kort, Michael E.,Atkinson, Robert N.,Thomas, James B.,Drizin, Irene,Johnson, Matthew S.,Secrest, Matthew A.,Gregg, Robert J.,Scanio, Marc J.C.,Shi, Lei,Hakeem, Ahmed H.,Matulenko, Mark A.,Chapman, Mark L.,Krambis, Michael J.,Liu, Dong,Shieh, Char-Chang,Zhang, Xufeng,Simler, Gricelda,Mikusa, Joseph P.,Zhong, Chengmin,Joshi, Shailen,Honore, Prisca,Roeloffs, Rosemarie,Werness, Stephen,Antonio, Brett,Marsh, Kennan C.,Faltynek, Connie R.,Krafte, Douglas S.,Jarvis, Michael F.,Marron, Brian E.
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scheme or table
p. 6812 - 6815
(2011/01/04)
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- Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain
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Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an NavL8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 v1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed > 100-fold selectivity versus human sodium (Na v1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.
- Kort, Michael E.,Drizin, Irene,Gregg, Robert J.,Scanio, Marc J. C.,Shi, Lei,Gross, Michael F.,Atkinson, Robert N.,Johnson, Matthew S.,Pacofsky, Gregory J.,Thomas, James B.,Carroll, William A.,Krambis, Michael J.,Liu, Dong,Shieh, Char-Chang,Zhang, XuFeng,Hernandez, Gricelda,Mikusa, Joseph P.,Zhong, Chengmin,Joshi, Shailen,Honore, Prisca,Roeloffs, Rosemarie,Marsh, Kennan C.,Murray, Bernard P.,Liu, Jinrong,Werness, Stephen,Faltynek, Connie R.,Krafte, Douglas S.,Jarvis, Michael F.,Chapman, Mark L.,Marron, Brian E.
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p. 407 - 416
(2008/09/18)
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