New isomeric classes of topically active ocular hypotensive carbonic anhydrase inhibitors: 5-substituted thieno[2,3-b]thiophene-2-sulfonamides and 5-substituted thieno[3,2-b]thiophene-2-sulfonamides.
A series of 5-substituted thieno[2,3-b]- and thieno[3,2-b)- and thieno[3,2-b)thiophene-2-sulfonamides was prepared and evaluated for topical ocular hypotensive activity in glaucoma models. The 5-substituents were varied to maximize both inhibitory potency against carbonic anhydrase and water solubility. At the same time, these substituents were varied in order to obtain compounds with the appropriate pKa to minimize pigment binding in the iris. All of these variables were optimized in the best compound, 5-[[(methoxyethyl)[(methoxyethyl)ethyl] amino]methyl]thieno[2,3-b]thiophene-2-sulfonamide hydrochloride (55).
Prugh
J D
JD
Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
Hartman
G D
GD
Mallorga
P J
PJ
McKeever
B M
BM
Michelson
S R
SR
Murcko
M A
MA
Schwam
H
H
Smith
R L
RL
Sondey
J M
JM
Springer
J P
JP
D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005901:Glaucoma / Q000188:drug therapy*; D066298:In Vitro Techniques; D007536:Isomerism; D008958:Models, Molecular; D015814:Ocular Hypotension / Q000188:drug therapy*; D011817:Rabbits; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; C069650:5-(((methoxyethyl)((methoxyethoxy)ethyl)amino)methyl)thieno(2,3-b)thiophene-2-sulfonamide