Synthesis and physicochemical properties of thiadiazolo[3,2-a]pyrimidinesulfonamides and thiadiazolo[3,2-a]triazinesulfonamides as candidates for topically effective carbonic anhydrase inhibitors.
A series of bicyclic 1,3,4-thiadiazolo[3,2-a]pyrimidine- and 1,3,4-thiadiazolo[3,2-a]triazine-7-sulfonamides were synthesized from 5-amino-1,3,4-thiadiazole-2-sulfonamide and evaluated for topical efficacy as ocular hypotensive agents. The compounds were tested for the physicochemical properties of sulfonamide pKa, free acid water solubility, CHCl3/buffer partition, and transcorneal penetration (kin), as well as for activity against carbonic anhydrase (I50). A number of these compounds exhibited lower sulfonamide pKa and higher water solubility than those of acetazolamide (1) and methazolamide (2), and one, 12, brought about a small reduction in IOP in the normal rabbit eye.
Katritzky
A R
AR
Department of Chemistry, University of Florida, Gainesville 32611.
Caster
K C
KC
Maren
T H
TH
Conroy
C W
CW
Bar-Ilan
A
A
D000287:Administration, Topical; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013830:Thiadiazoles; D014227:Triazines