Topically active carbonic anhydrase inhibitors. 1. O-acyl derivatives of 6-hydroxybenzothiazole-2-sulfonamide.

A series of O-acyl derivatives of 6-hydroxybenzothiazole-2-sulfonamide (4, L-643,799) was prepared and the potential utility of each series member as a topically active inhibitor of ocular carbonic anhydrase was determined. In vitro studies showed these esters to be substrates for ocular esterases which liberate 4 during corneal translocation. The most interesting series member, 2-sulfamoyl-6-benzothiazolyl 2,2-dimethylpropionate (22, L-645,151), acting as a prodrug form of 4, was found to enhance delivery through the isolated albino rabbit cornea by 40-fold when compared to the parent phenol 4.

Design, synthesis, and testing of potential antisickling agents. 7. Ethacrynic acid analogues.

In search of a drug to treat sickle cell anemia, several analogues of the diuretic ethacrynic acid (ECA) have been synthesized and found equivalent in antigelling potency to ECA, but they have moderate or little diuretic activity. Structure-activity studies revealed that most of the highly active derivatives contain an acryloyl moiety. The latter functionality reacts covalently with protein sulfhydryl groups via a Michael addition reaction.

Intracellular accumulation of potent amiloride analogues by human neutrophils.

The mechanism of uptake of a series of amiloride derivatives by human neutrophils was investigated using [14C]amiloride and the 14C-labeled 5-(1-hexahydroazepinyl)-6-bromo analogue (BrMM) which is approximately 500-fold more potent than the parent compound at inhibiting Na+/H+ exchange. At an external concentration of 2 microM, the influx of BrMM at 37 degrees C was rapid, reaching a steady state by approximately 20 min. The rate of BrMM uptake (approximately 25 mumol/liter.

Improved recovery from a traumatic-hypoxic brain injury in cats by intracisternal injection of an anion transport inhibitor.

Cats, injured by a mechanical plus hypoxic model of traumatic brain injury, were treated by intracisternal injection of a modified loop diuretic (L-644,711). This drug inhibits the chloride/bicarbonate anion exchange transport system. The treatment resulted in a significant decrease in mortality from 61 to 21%, and an improvement in both neurological status and EEG activity of the surviving animals.

Agents for the treatment of brain edema. 2. [(2,3,9,9a-Tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]+ ++alkanoi c acids and some of their analogues.

Our initial paper discussed brain edema resulting from traumatic head injury and the need for specific and effective agents to treat the disorder and disclosed a novel approach for the discovery of a drug of this kind. The current study describes the synthesis of a series of [(2,3,9,9a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alk anoic acids and their analogues. These compounds were evaluated in an in vitro cerebrocortical tissue slice assay for their relative potencies in inhibiting K+ + HCO3- induced swelling.