title: Novel inhibitors of the Gardos channel for the treatment of sickle cell disease.
abstract: 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.
authors.affiliation: Icagen, Inc., Post Office Box 14487, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McNaughton-Smith
authors.forename: J Ford
authors.initials: JF
authors.lastname: Burns
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Stocker
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Rigdon
authors.forename: Christopher
authors.initials: C
authors.lastname: Creech
authors.forename: Susan
authors.initials: S
authors.lastname: Arrington
authors.forename: Tara
authors.initials: T
authors.lastname: Shelton
authors.forename: Lucia
authors.initials: L
authors.lastname: de Franceschi
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D000818:Animals; D001682:Biological Availability; D003022:Clotrimazole / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008297:Male; D051379:Mice; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014320:Triphenylmethyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000081:Acetamides; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D014320:Triphenylmethyl Compounds; D003022:Clotrimazole; C472774:senicapoc