2842-37-7Relevant articles and documents
Discovery of Axelopran (TD-1211): A Peripherally Restricted μ-Opioid Receptor Antagonist
Armstrong, Scott R.,Beattie, David T.,Campbell, Christina B.,Church, Timothy J.,Colson, Pierre-Jean,Dalziel, Sean M.,Jacobsen, John R.,Jiang, Lan,Long, Daniel D.,Obedencio, Glenmar P.,Rapta, Miroslav,Saito, Daisuke,Stergiades, Ioanna,Tsuruda, Pamela R.,Van Dyke, Priscilla M.,Vickery, Ross G.
supporting information, (2019/12/11)
The effects of opioids in the central nervous system (CNS) provide significant benefit in the treatment of pain but can also lead to physical dependence and addiction, which has contributed to a growing opioid epidemic in the United States. Gastrointestinal dysfunction is an additional serious consequence of opioid use, and this can be treated with a localized drug distribution of a non-CNS penetrant, peripherally restricted opioid receptor antagonist. Herein, we describe the application of Theravance's multivalent approach to drug discovery coupled with a physicochemical property design strategy by which the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenyl carboxamide series of μ-opioid receptor antagonists was optimized to afford the orally absorbed, non-CNS penetrant, Phase 3 ready clinical compound axelopran (TD-1211) 19i as a potential treatment for opioid-induced constipation.
Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping
Ji, Haitao,Li, Huiying,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
experimental part, p. 779 - 797 (2009/12/07)
Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity but more druglike properties can be achieved by fragment hopping. On the basis of the structure of lead molecule 6, fragment hopping effectively extracted the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better druglike properties were obtained within the design of 20 derivatives (compounds 7-26). Our structure - based inhibitor design for nNOS and SAR analysis reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this approach to many other therapeutic targets for which known druglike small-molecule modulators are still limited.
Synthesis and biological evaluation of thiazolidine-2-one 1,1-dioxide as inhibitors of Escherichia coli β-ketoacyl-ACP-synthase III (FabH)
Alhamadsheh, Mamoun M.,Waters, Norman C.,Huddler, Donald P.,Kreishman-Deitrick, Mara,Florova, Galina,Reynolds, Kevin A.
, p. 879 - 883 (2007/10/03)
A series of cyclic sulfones has been synthesized and their activity against β-ketoacyl-ACP-synthase III (FabH) has been investigated. The compounds are selectively active against Escherichia coli FabH (ecFabH), but not Mycobacterium tuberculosis FabH (mtFabH) or Plasmodium falciparum KASIII (PfKASIII). The activity against ecFabH ranges from 0.9 to >100 μM and follows a consistent general SAR trend. Many of the compounds were shown to have antimalarial activity against chloroquine (CQ)-sensitive (D6) P. falciparum (IC50 = 5.3 μM for the most potent inhibitor) and some were active against E. coli (MIC = 6.6 μg/ml for the most potent inhibitor).
