+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Carbonic anhydrase inhibitors. Part 71 Synthesis and ocular pharmacology of a new class of water-soluble, topically effective intraocular pressure lowering sulfonamides incorporating picolinoyl moieties

, : Carbonic anhydrase inhibitors. Part 71 Synthesis and ocular pharmacology of a new class of water-soluble, topically effective intraocular pressure lowering sulfonamides incorporating picolinoyl moieties. European Journal of Pharmaceutical Sciences 8(4): 317-328, Aug

Reaction of 20 aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with picolinic acid in the presence of carbodiimide derivatives afforded a series of water-soluble (as hydrochloride or triflate salts) compounds. The new derivatives were assayed as inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form). Efficient inhibition was observed against all three isozymes, but especially against CA II and CA IV (in nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% water solutions directly into the eye of normotensive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP) lowering was observed for many of them, and the active drug was detected in eye tissues and fluids. This result prompted us to reanalyze the synthetic work done by other groups for the design of water soluble, topically effective antiglaucoma sulfonamides. According to these researchers, the IOP lowering effect is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sulfonamide derivatives represent the best studied case. Indeed, the first agents developed for such applications, such as dorzolamide, are derivatives of this ring system. In order to prove that the tail (in this case the picolinoyl moiety) conferring water solubility to a sulfonamide CA inhibitor is critically important for its topical effectiveness, similarly to the ring to which the sulfonamido group is grafted, we also prepared a dorzolamide derivative to which the picolinoyl moiety was attached. This new compound is more water soluble than dorzolamide (as hydrochloride salt), behaves as a strong CA II inhibitor, and acts similarly to the parent derivative in lowering IOP in experimental animals. Thus, it seems that the tail conferring water solubility is more important for topical activity as antiglaucoma drug, than the heterocyclic/aromatic ring to which the sulfonamido moiety is grafted.


PMID: 10425382

DOI: 10.1016/s0928-0987(99)00022-6

Other references

van der Gaag, E., 2014: Molluscum contagiosum clearance following a dietary change. Cutis 92(4): E3-E4

Lemos, M.; Regataeiro, F., 1998: Relationship between polymorphism at the CYP2D6 locus and susceptibility to haematological neoplasias. European Journal of Human Genetics 6(SUPPL 1): 104

Chyna, J.T., 2001: Electronic medical records. Will the future of healthcare be paperless?. Healthcare Executive 15(4): 14-20

Bleumink, E., 1966: Milk allergy. The atopic allergen in cows' milk. This article reviews and presents the salient points of the research work on the atopic allergen in cows' milk carried out at the State University in Utrecht.

Lorenz, Felix., 2000: Contribution to the knowledge on the ring cowry Erosaria annulus Linnaeus 1758 and related species Mollusca Gastropoda Cypraeidae Beitrage zur Kenntnis der Ringkauri Erosaria annulus Linnaeus 1758 und verwandter Arten Mollusca Gastropoda Cypraeidae. Schriften zur Malakozoologie aus dem Haus der Natur-Cismar, 14: 1-95

Kern, R., 1978: Complications and their prevention before, during and after the implantation of intraocular lenses. The complications and their prevention during and after the implantation of iris clip- and iridocapsular lenses are evaluated. The follow-up period varied from 6-72 months. A careful selection of the patients and optimal conditions during the oper...

Mabrouk, A.; Ben Cheikh, H., 2015: Thymoquinone supplementation reverses lead-induced oxidative stress in adult rat testes. The purpose of the present study was to investigate the potential protective effect of thymoquinone (TQ), the major active ingredient of volatile oil of Nigella sativa seeds, against Pb-induced testicular oxidative stress. Adult male rats were ran...

Shiflett, A.M.; Faulkner, S.D.; Cotlin, L.F.; Widener, J.; Stephens, N.; Hajduk, S.L., 2007: African trypanosomes: intracellular trafficking of host defense molecules. Trypanosoma brucei brucei is the causative agent of Nagana in cattle and can infect a wide range of mammals but is unable to infect humans because it is susceptible to the innate cytotoxic activity of normal human serum. A minor subfraction of hu...

Das, G.; Augustine, M.M.; Das, J.; Bottomly, K.; Ray, P.; Ray, A., 2003: An important regulatory role for CD4+CD8 alpha alpha T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease. The normal immunoregulatory mechanisms that maintain homeostasis in the intestinal mucosa, despite continuous provocation by environmental antigens, are jeopardized in inflammatory bowel diseases. Although previous studies have suggested that inte...

Mayou, T.V., 1967: Paleontology of the Permian Loray Formation in White Pine County, Nevada. Geology Studies Brigham Young University, 14: 101-122