3-substituted thieno[2,3-b][1,4]thiazine-6-sulfonamides. A novel class of topically active carbonic anhydrase inhibitors.
3-Aminoalkyl derivatives of thieno[2,3-b][1,4]thiazine-6-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. The compounds described were found to be excellent in vitro inhibitors of carbonic anhydrase II and in vivo to lower intraocular pressure in three rabbit models of ocular hypertension. Compounds 20A, 20B, and 20C met the requirement of formulation as a 1% solution at pH 5.2, but none of the compounds described exhibited greater activity in the normotensive albino rabbit, the alpha-chymotrypsin-treated albino rabbit, or the normotensive pigmented rabbit than MK-927 or MK-507, the present clinical candidates.
Hunt
C A
CA
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
Mallorga
P J
PJ
Michelson
S R
SR
Schwam
H
H
Sondey
J M
JM
Smith
R L
RL
Sugrue
M F
MF
Shepard
K L
KL
D000287:Administration, Topical; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects*; D008958:Models, Molecular; D011817:Rabbits; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides