Novel inhibitors of the Gardos channel for the treatment of sickle cell disease.
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.
McNaughton-Smith
Grant A
GA
Icagen, Inc., Post Office Box 14487, Research Triangle Park, North Carolina 27709, USA.
Burns
J Ford
JF
Stocker
Jonathan W
JW
Rigdon
Gregory C
GC
Creech
Christopher
C
Arrington
Susan
S
Shelton
Tara
T
de Franceschi
Lucia
L
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
D000081:Acetamides; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D014320:Triphenylmethyl Compounds; D003022:Clotrimazole; C472774:senicapoc