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

J D Prugh; G D Hartman; P J Mallorga; B M McKeever; S R Michelson; M A Murcko; H Schwam; R L Smith; J M Sondey; J P Springer

doi:10.1021/jm00110a008

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

J Med Chem. 1991 Jun;34(6):1805-18. doi: 10.1021/jm00110a008.

Authors

J D Prugh¹, G D Hartman, P J Mallorga, B M McKeever, S R Michelson, M A Murcko, H Schwam, R L Smith, J M Sondey, J P Springer, et al.

Affiliation

¹ Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.

PMID: 2061922
DOI: 10.1021/jm00110a008

Abstract

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).

MeSH terms

Animals
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / pharmacology*
Glaucoma / drug therapy*
In Vitro Techniques
Isomerism
Models, Molecular
Ocular Hypotension / drug therapy*
Rabbits
Sulfonamides / chemical synthesis
Sulfonamides / pharmacology*
Thiophenes / chemical synthesis
Thiophenes / pharmacology*

Substances

Carbonic Anhydrase Inhibitors
Sulfonamides
Thiophenes
5-(((methoxyethyl)((methoxyethoxy)ethyl)amino)methyl)thieno(2,3-b)thiophene-2-sulfonamide