Sulfonamides as potassium channel blockers

#This invention relates to the use of sulfonamides as potassium channel blockers and to the treatment of diseases modulated by potassium channels. Additionally, this invention relates to sulfonamide compounds that are useful as potassium channel blockers.

#Ion channels are cellular proteins that regulate the flow of ions, including calcium, potassium, sodium and chloride into and out of cells. These channels are present in all human cells and affect such physiological processes as nerve transmission, muscle contraction, cellular secretion, regulation of heartbeat, dilation of arteries, release of insulin, and regulation of renal electrolyte transport. Among the ion channels, potassium channels are the most ubiquitous and diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive, and epithelial tissue. These channels allow the flow of potassium in and/or out of the cell under certain conditions. For example, the outward flow of potassium ions upon opening of these channels makes the interior of the cell more negative, counteracting depolarizing voltages applied to the cell. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands, and ATP-sensitivity.

#Potassium channels are made by alpha subunits that fall into at least 8 families, based on predicted structural and functional similarities (Wei et al., Neuropharmacology 35(7): 805–829 (1997)). Three of these families (Kv, eag-related, and KQT) share a common motif of six transmembrane domains and are primarily gated by voltage. Two other families/ also contain this motif but are gated by cyclic nucleotides (CNG) and calcium (small conductance and intermediate conductance potassium channels), respectively. The small conductance and intermediate conductance, calcium activated potassium channels comprise a family of calcium activated potassium channels gated solely by calcium, with a unit conductance of 2-20 and 20-85 pS, respectively. Macroscopic and unitary intermediate conductance, calcium activated potassium channel currents show inward rectification (see, e.g., Ishii et al., Proc. Natl. Acad. Sci USA 94: 11651–11656 (1997). The three other families of potassium channel alpha subunits have distinct patterns of transmembrane domains. Slo family potassium channels, or BK channels have seven transmembrane domains (Meera et al., Proc. Natl. Acad. Sci. U.S.A. 94(25): 14066–71 (1997)) and are gated by both voltage and calcium or pH (Schreiber et al., J. Biol. Chem. 273: 3509–16 (1998)). Another family, the inward rectifier potassium channels (Kir), belongs to a structural family containing two transmembrane domains, and an eighth functionally diverse family (TP, or “two-pore”) contains two tandem repeats of this inward rectifier motif.

#FIGURE 1 displays structures of representative compounds of the invention.

#Abbreviations and Definitions

#The abbreviations used herein have their conventional meaning within the chemical and biological arts. For example: Et3N, triethylamine; MeOH, methanol; and DMSO, dimethylsulfoxide; MCHC, mean corpuscular hemoglobin concentration; SAD-1, a transgenic mouse model of sickle cell disease as described by Trudel et. al., EMBO J., 10 (11): 3157–3165 (1991).

#“Blocking” and “inhibiting,” are used interchangeably herein to refer to the partial or full blockade of an intermediate conductance, calcium activated potassium channel by one or more compound(s) of the invention.