Discovery, Synthesis, and Structure Activity Relationship of a Series of N-Aryl- bicyclo[2.2.1]heptane-2-carboxamides: Characterization of ML213 as a Novel KCNQ2 and KCNQ4 Potassium Channel Opener.

Herein we report the discovery, synthesis and evaluation of a series of N-Aryl-bicyclo[2.2.1]heptane-2-carboxamides as selective KCNQ2 (K(v)7.2) and KCNQ4 (K(v)7.4) channel openers. The best compound, 1 (ML213) has an EC(50) of 230 nM (KCNQ2) and 510 nM (KCNQ4) and is selective for KCNQ2 and KCNQ4 channels versus a large battery of related potassium channels, as well as affording modest brain levels. This represents the first report of unique selectivity profile for KCNQ2 and KCNQ4 over the other channels (KCNQ1/3/5) and as such should prove to be a valuable tool compound for understanding these channels in regulating neuronal activity.

[1]  Robin J. Leach,et al.  A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family , 1998, Nature Genetics.

[2]  Fan Zhang,et al.  Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7/KCNQ potassium channel activators. , 2011, European journal of medicinal chemistry.

[3]  William T. Harrison,et al.  Novel KCNQ2/Q3 agonists as potential therapeutics for epilepsy and neuropathic pain. , 2010, Journal of medicinal chemistry.

[4]  R. Bradshaw.  Methionine aminopeptidase 2 inhibition: antiangiogenesis and tumour therapy , 2004 .

[5]  D. A. Brown,et al.  Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone , 1980, Nature.

[6]  James O McNamara,et al.  In Vivo Profile of ICA-27243 [N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide], a Potent and Selective KCNQ2/Q3 (Kv7.2/Kv7.3) Activator in Rodent Anticonvulsant Models , 2008, Journal of Pharmacology and Experimental Therapeutics.

[7]  Mark J. Suto,et al.  N-Pyridyl and Pyrimidine Benzamides as KCNQ2/Q3 Potassium Channel Openers for the Treatment of Epilepsy. , 2011, ACS medicinal chemistry letters.

[8]  Qi Gao,et al.  Synthesis and KCNQ2 opener activity of N-(1-benzo[1,3]dioxol-5-yl-ethyl, N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl, and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl acrylamides. , 2004, Bioorganic & medicinal chemistry letters.

[9]  W. Dalby-Brown,et al.  Kv7 (KCNQ) channel modulators and neuropathic pain. , 2007, Journal of medicinal chemistry.

[10]  W. Alves,et al.  Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures , 2007, Neurology.

[11]  M. Leppert,et al.  KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. , 2003, Brain : a journal of neurology.

[12]  V. Gribkoff.  The therapeutic potential of neuronal KV7 (KCNQ) channel modulators: an update , 2008 .

[13]  W. Löscher,et al.  D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures , 1996, Epilepsy Research.

[14]  Mark Leppert,et al.  A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns , 1998, Nature Genetics.

[15]  C. Rundfeldt.  The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. , 1997, European journal of pharmacology.

[16]  Meng Wu,et al.  Isoform-specific Prolongation of Kv7 (KCNQ) Potassium Channel Opening Mediated by New Molecular Determinants for Drug-Channel Interactions* , 2010, The Journal of Biological Chemistry.

[17]  Astrid A. Ortiz,et al.  Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels , 2001, Nature Medicine.

[18]  Q. Xiong,et al.  Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds. , 2008, Trends in pharmacological sciences.