- Discovery of Axelopran (TD-1211): A Peripherally Restricted μ-Opioid Receptor Antagonist
-
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.
- 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)
-
- Enantioselective Radical Cyclization for Construction of 5-Membered Ring Structures by Metalloradical C-H Alkylation
-
Radical cyclization represents a powerful strategy for construction of ring structures. Traditional radical cyclization, which is based on radical addition as the key step, necessitates the use of unsaturated substrates. Guided by the concept of metalloradical catalysis, a different mode of radical cyclization that can employ saturated C-H substrates is demonstrated through the development of a Co(II)-based system for catalytic activation of aliphatic diazo compounds for enantioselective radical alkylation of various C(sp3)-H bonds. It allows for efficient construction of chiral pyrrolidines and other valuable 5-membered cyclic compounds. This alternative strategy of radical cyclization provides a new retrosynthetic paradigm to prepare five-membered cyclic molecules from readily available open-chain aldehydes through the union of C-H and C=O elements for C-C bond formation.
- Wang, Yong,Wen, Xin,Cui, Xin,Zhang, X. Peter
-
supporting information
p. 4792 - 4796
(2018/04/17)
-
- Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping
-
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.
- Ji, Haitao,Li, Huiying,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
-
experimental part
p. 779 - 797
(2009/12/07)
-
- Synthesis and biological evaluation of thiazolidine-2-one 1,1-dioxide as inhibitors of Escherichia coli β-ketoacyl-ACP-synthase III (FabH)
-
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).
- Alhamadsheh, Mamoun M.,Waters, Norman C.,Huddler, Donald P.,Kreishman-Deitrick, Mara,Florova, Galina,Reynolds, Kevin A.
-
p. 879 - 883
(2007/10/03)
-
- Phenylpropanoic acid derivatives bearing a benzothiazole ring as PPARδ-selective agonists
-
To find novel PPARδ-selective agonists, we designed and synthesized phenylpropanoic acid derivatives bearing 6-substituted benzothiazoles. Optimization of this series led to the identification of a potent and selective PPARδ agonist 17. Molecular modeling suggested that compound 17 occupies the Y-shaped pocket of PPARδ appropriately.
- Fujieda, Hiroki,Usui, Shinya,Suzuki, Takayoshi,Nakagawa, Hidehiko,Ogura, Michitaka,Makishima, Makoto,Miyata, Naoki
-
p. 4351 - 4357
(2008/02/12)
-
- 8-Azabicyclo[3.2.1]octane compounds as mu opioid receptor antagonists
-
The invention provides novel 8-azabicyclo[3.2.1]octane compounds of formula (I): wherein R1, R2, R3, A, and G are defined in the specification, or a pharmaceutically-acceptable salt or solvate thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 23-24
(2008/06/13)
-
- OPHTHALMIC COMPOSITIONS FOR TREATING OCULAR HYPERTENSION
-
This invention relates to the use of potent potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which leads to elevated intraoccular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.
- -
-
Page/Page column 34
(2008/06/13)
-
- NOVEL OXABISPIDINE COMPOUNDS AND THEIR USE IN THE TREATMENT OF CARDIAC ARRHYTHMIAS
-
There is provided compounds of formula I, wherein R1, R2, R4, R41 to R46, A, B and G have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.
- -
-
Page/Page column 67-68
(2008/06/13)
-
- Structural studies on bioactive compounds. 34.1 Design, synthesis, and biological evaluation of triazenyl-substituted pyrimethamine inhibitors of Pneumocystis carinii dihydrofolate reductase
-
The triazenyl-pyrimethamine derivative 3a (TAB), a potent and selective inhibitor of Pneumocystis carinii DHFR, was selected as the starting point for a lead optimization study. Molecular modeling studies, corroborated by a recent crystal structure determination of the ternary complex of P. carinii DHFR-NADPH bound to TAB, predicted that modifications to the acetoxy residue of the lead inhibitor could exploit binding opportunities in the vicinity of an active site pocket bounded by residues Ile33, Lys37, and Leu72. Substitutions in the benzyl moiety with electron-donating and electron-withdrawing groups were predicted to probe face-edge interactions with amino acid Phe69 unique to the P. carinii enzyme. New triazenes 10a-v and 12a-f were prepared by coupling the diazonium tetrafluoroborate salt 6b of aminopyrimethamine with substituted benzylamines or phenethylamines. The most potent of the new inhibitors against P. carinii DHFR was the naphthylmethyl-substituted triazene 10t (IC50: 0.053 μM), but a more substantial increase in potency against the rat liver DHFR led to a reduction in selectivity (ratio rat liver DHFR IC50/P. carinii DHFR IC50: 5.36) compared to the original lead structure 3a (ratio rat liver DHFR IC50/P. carinii DHFR IC50: 114).
- Chan,Laughton,Queener,Stevens
-
p. 2555 - 2564
(2007/10/03)
-