Sickle cell disease (SCD) is a hereditary condition characterized by deformation of red blood cells (RBCs). This phenomenon is due to the presence of abnormal hemoglobin that polymerizes upon deoxygenation. This effect is exacerbated when dehydrated RBCs experience a loss of both water and potassium salts. One critical pathway for the regulation of potassium efflux from RBCs is the Gardos channel, a calcium-activated potassium channel. This paper describes the synthesis and biological evaluation of a series of potent inhibitors of the Gardos channel. The goal was to identify compounds that were potent and selective inhibitors of the channel but had improved pharmacokinetic properties compared to 1, Clotrimazole. Several triarylamides such as 10 and 21 were potent inhibitors of the Gardos channel (IC50 of <10 nM) and active in a mouse model of SCD. Compound 21 (ICA-17043) was advanced into phase 3 clinical trials for SCD.

Current drugs for the treatment of seizure disorders, although effective in many patients, still suffer from a number of failures and are not effective in some forms of resistant epilepsies. Historically, many of these drugs have multiple mechanisms of action including calcium and sodium channel blockade as well as GABAergic activity and thus a number of associated side effects. Modulation of the M-current through opening of KCNQ channels has been proposed as a way to attenuate neuroexcitability and have a therapeutic benefit for the treatment of seizure disorders. Therefore, as part of our program to identify new treatments for epilepsy, we set out to identify agonists of KCNQ channels. High throughput screening of our corporate collection led to the identification of 1, adamantane-1-carboxylic acid (3-methyl-3H-benzothiazol-2-ylidine) hydrazide, a potent KCNQ2/Q3 agonist. Herein, we describe the syntheses and structure-activity relationships of analogues of 1 as well as their in vivo activity in animal models of epilepsy and neuropathic pain.

The synthetic methods reported in the literature for the preparation of sulfonylureas tend to be restricted in scope or unsuitable for use in parallel synthesis. We have developed a method for preparing sterically congested sulfonylureas based on N,N'-sulfuryldiimidazole that is both convenient and amenable to parallel synthesis. Sequential activation by way of alkylation of the imidazole group using methyl triflate followed by nucleophilic displacement with a variety of amines and anilines afford the unsymmetrical sulfonylurea. Sulfonylureas prepared from anilines were obtained in high yields using N,N'-sulfuryldiimidazole, while the somewhat more sterically congested analogue, N,N'-sulfurylbis-2-methylimidazole, proved to be superior for alkylamines.

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