353293-50-2Relevant articles and documents
Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators
Surur, Abdrrahman S.,Bock, Christian,Beirow, Kristin,Wurm, Konrad,Schulig, Lukas,Kindermann, Markus K.,Siegmund, Werner,Bednarski, Patrick J.,Link, Andreas
supporting information, p. 4512 - 4522 (2019/05/17)
Drug induced liver injury (DILI) and tissue discoloration led to the recent discontinuation of the therapeutic use of the closely related drugs flupirtine and retigabine, respectively. Experience gained with these drugs strongly suggests that heterotetramer, voltage-gated potassium channels 2 and 3 (KV7.2/3) are valid targets for effective treatment of pain and epilepsy. Because the adverse effects are not related to the mechanism of action, it appears promising to investigate chemical modifications of these clinically validated, drug-like leads. In the present retro-metabolic drug design study, a series of 43 compounds were synthesized and characterized with regard to KV7.2/3 opening activity and efficacy. The most active compound 22d displays excellent potency (EC50 = 4 nM) and efficacy (154%) as a KV7.2/3 opener. Limited aqueous solubility hampered toxicity testing at concentrations higher than 63 μM, but this concentration was nontoxic to two hepatocellular cell lines (HEP-G2 and TAMH) in culture. The slightly less active but more soluble compound 25b (EC50 = 11 nM, efficacy 111%) showed an improved toxicity/activity ratio compared to flupirtine by three orders of magnitude and represents an attractive lead structure for the development of safer analgesics and antiepileptics.
Ortho-selectivity in the nucleophilic aromatic substitution (S NAr) reactions of 3-substituted, 2,6-dichloropyridines with alkali metal alkoxides
Yap, Jeremy L.,Hom, Kellie,Fletcher, Steven
scheme or table, p. 4172 - 4176 (2011/09/19)
3-Substituted, 2,6-dichloropyridines have featured in the syntheses of small molecule inhibitors of a wide variety of biological targets. Hence, the regioselective displacement of the chlorines is of significant interest. Through conducting an extensive solvent study, we have found that non-polar, aprotic solvents of low hydrogen bond basicities favour substitution of the chlorine ortho to the 3-substituent by alkali metal alkoxides. We present convincing evidence that coordination of the alkali metal counter-ion to the 3-substituent (nitro, ester, amide) is the origin of the ortho-selectivity to give a cyclic, six-membered transition state. Excellent ortho-selectivities (≥98:2) for secondary and tertiary alkoxides were realized with the sodium counter-ion, whereas the more reactive primary alkoxides required the harder, more Lewis acidic lithium counter-ion.
Design and application of an α-helix-mimetic scaffold based on an oligoamide-foldamer strategy: Antagonism of the Bak BH3/Bcl-xL complex
Ernst, Justin T.,Becerril, Jorge,Park, Hyung Soon,Yin, Hang,Hamilton, Andrew D.
, p. 535 - 539 (2007/10/03)
The prevention of cell death by the antiapoptotic protein Bcl-xL has been linked to a number of cancers. Bcl-xl binds to the BH3 domain of the proapoptotic protein Bak, thus preventing programmed cell death. A competitive assay and docking studies have shown that the polyamide scaffold 1, which was synthesized based on a rational structure-based design, interferes with the Bak BH3/Bcl-xl complexation.
