Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0595921 (intraocular pressure)
 11,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:3-substituted thieno[2,3-b][1,4]thiazine-6-sulfonamides. A novel class of topically active carbonic anhydrase inhibitors. 829 11

We have assessed the onset and duration of decreased intraocular pressure and aqueous humor flow contrasting systemic and topical administration of carbonic anhydrase inhibitors. The relationship between physiological effects and fractional activity of carbonic anhydrase isoenzymes in the eye was also investigated. Experiments were performed in normotensive New Zealand white rabbits. Intraocular pressure was determined manometrically or tonometrically and aqueous humor flow by sulfacetamide clearance. We studied methazolamide (25 mg kg-1), ethoxzolamide (4 mg kg-1), and MK-927 (2% in 0.5% hydroxyethylcellulose, topical, pH 4.8). There is an immediate reduction in intraocular pressure (1.2 and 1.8 mmHg by 2 min) and aqueous flow (33% and 40% by 5 min) following intravenous dosing with either methazolamide or ethoxzolamide. This correlates with rapid appearance of drug in the anterior uvea and very low fractional activity of ocular carbonic anhydrase isoenzymes II (cytosolic) and IV (membrane bound). Peak intraocular pressure reduction averaged 4.2 +/- 0.68 mmHg and 4.5 +/- 0.8 mmHg for methazolamide and ethoxzolamide at 60 and 45 min, respectively. Peak flow reduction was 38% for methazolamide and 40% for ethoxzolamide, at 5 min. Aqueous flow and intraocular pressure returned to baseline at 7 and 4 hr following methazolamide and ethoxzolamide, respectively. This corresponds to decay of drug from ocular tissues and significant increases in fractional activity of carbonic anhydrase isoenzymes. Topical MK-927 resulted in a 1.2 mmHg decrease in pressure by 5 min. This correlated with the early appearance of drug in the anterior uvea prior to its appearance in aqueous humor and very low fractional activity of carbonic anhydrase isoenzymes. Intraocular pressure decreased 3.6 +/- 0.35 mmHg at 1 hr and returned to baseline by 6 hr. Aqueous flow was reduced 12% by 5 min and 35% at 1 hr. The appearance of MK-927 in the anterior uvea prior to detection in aqueous suggests a significant non-corneal route of absorption following topical administration. Topical MK-927 results in a more gradual reduction in intraocular pressure and flow, although peak effects are not statistically different from systemic carbonic anhydrase inhibitors. The time of pressure return to baseline is also comparable to systemic carbonic anhydrase inhibitors. Because the relations between carbonic anhydrase II and carbonic anhydrase IV in the ciliary process are not yet clear and since the drugs have different affinities for the isozymes, the precise degree of fractional inhibition necessary for pharmacological effect is not certain, but based on drug concentration in the anterior uvea, may take 98% inhibition for full intraocular pressure reduction.
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PMID:A comparison between the effect of topical and systemic carbonic anhydrase inhibitors on aqueous humor secretion. 840 74

Organic sulfamates are a new variation to the carbonic anhydrase (CA) inhibitor structure-action relationship. Inhibitory activity is conferred by the classic sulfonamide group, but through linkage to the benzene ring by an oxygen. AHR-16329, a representative sulfamate, has an acidic (sulfonamide, pKa 8.9) and basic (imidazole, pKa 6.0) group and has desirable physicochemical properties for topical intraocular pressure lowering: good water solubility below pH 6.0, a CHCl3/buffer ratio of 0.5 at pH 7.0 and a Kl against CA-II of 7 nM. Inhibition of CO2 hydration is noncompetitive. When applied locally to the eye, AHR-16329 reaches significant levels in ocular tissues and fluids and reduces significantly intraocular pressure. Five percent concentration gives the greatest reduction, equivalent to systemic inhibitors; 2 and 5% have similar pressure x time duration. These studies expand structure-action relations in the field of CA inhibitors and the validity of developing topical CA inhibitors for treatment of glaucoma.
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PMID:Carbonic anhydrase inhibitory activity and ocular pharmacology of organic sulfamates. 843 14

There was a time gap of over 40 years between the demonstrated oral effectiveness of acetazolamide in lowering the intraocular pressure (IOP) of glaucoma patients and the introduction of a topical carbonic anhydrase (CA) inhibitor. This is due to the fact that CA-II, the isoenzyme which most likely plays an important role in the production of aqueous humor in humans, must be essentially inhibited by 100% to elicit a pharmacological response. The lack of success with earlier attempts to obtain a topical agent stems from an inability to attain and maintain a sufficiently high intraocular concentration of drug to achieve the required inhibition of CA. Dorzolamide and brinzolamide are two topical CA inhibitors which are currently available to treat ocular hypertension and/or glaucoma. Dorzolamide is a very potent inhibitor of CA-II and its site of action is local within the eye. Like oral CA inhibitors, topically applied dorzolamide lowers IOP by decreasing the production of aqueous humor. The drug is used in monotherapy as a 2% solution administered three times daily. Its ocular hypotensive effect is comparable to that of timolol at peak but is somewhat less at trough. The IOP lowering effect of timolol is enhanced by the twice daily administration of 2% dorzolamide either concomitantly or in combination. Topically applied dorzolamide is generally well tolerated and had a low drop-out rate in clinical studies. The most frequent ocular adverse experience is burning and/or stinging. Corneal and lenticular problems have generally not been encountered with long-term therapy with dorzolamide. Topically applied dorzolamide penetrates directly to the posterior segment of the eye and its presence is consistent with the initial report that dorzolamide increases retinal blood flow velocity in patients with normal tension glaucoma. The most frequent systemic adverse experience is a transient bitter taste. Biochemical changes indicative of the systemic inhibition of CA have not been observed in monotherapy studies lasting up to 2 years. This is in harmony with the inability of dorzolamide at steady-state to saturate CA in the red blood cell and the failure to detect its presence in plasma. A 1% suspension of brinzolamide is comparable to 2% dorzolamide in lowering IOP, both drugs being administered three times daily. Although brinzolamide has a lower incidence of burning/ stinging, it elicits more blurred vision.
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PMID:Pharmacological and ocular hypotensive properties of topical carbonic anhydrase inhibitors. 1061 82

Novel non-chiral 2H-thieno[3,2-e]- and [2,3-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides were synthesized for evaluation as potential candidates for the treatment of glaucoma. All of the compounds prepared were potent high affinity inhibitors of human carbonic anhydrase II, Ki < 0.5 nM. Additionally, inhibition of recombinant human carbonic anhydrase IV was determined for selected compounds; these were shown to be moderate to potent inhibitors of this isozyme with IC50 values ranging from 4.25 to 73.6 nM. Of the compounds evaluated for their ability to lower intraocular pressure in naturally hypertensive Dutch-belted rabbits, 5a, 17a3, 17b1, 17b2, 17h2 and 17i1 showed significant efficacy (> 20% decrease) in this model following topical ocular administration.
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PMID:2H-Thieno[3,2-e]- and [2,3-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides as ocular hypotensive agents: synthesis, carbonic anhydrase inhibition and evaluation in the rabbit. 1088 8

Carbonic anhydrase inhibitors are effective in lowering intraocular pressure, the primary indication of glaucoma. Human carbonic anhydrase II, and possibly carbonic anhydrase IV (CAII and CAIV, respectively), help regulate fluid secretion into the anterior chamber of the eye. Because inhibitors currently formulated as drugs to treat glaucoma were designed to target CAII, an understanding of the structural basis of CAII-CAIV discrimination by inhibitors would be useful for probing the role of each isozyme in the etiology of the disease. Here, we report the X-ray crystal structures of three novel thieno[3,2-e]-1,2-thiazine-6-sulfonamides complexed with CAII and the computationally predicted structures of the same compounds complexed with CAIV. All three compounds bind with similar affinity to CAII, but they bind with up to 100-fold lower affinities to CAIV. Comparisons of experimentally determined structures of CAII-inhibitor complexes and computationally predicted structures of CAIV-inhibitor complexes allow us to rationalize these affinity trends and outline molecular features that may contribute to high-affinity inhibitor binding to CAIV. This study demonstrates how experimental structure determination methods and computational structure prediction methods can be used together to answer questions that cannot be answered by either method alone.
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PMID:Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV. 1183

Selective inhibition of ciliary process enzyme i.e. Carbonic Anhydrase-II is an excellent approach in reducing elevated intraocular pressure, thus treating glaucoma. Due to characteristic physicochemical properties of sulphonamide (Inhibition of Carbonic Anhydrase), they are clinically effective against glaucoma. But the non-specificity of sulphonamide derivatives to isozyme, leads to a range of side effects. Presently, the absence of comparative studies related to the binding of the sulphonamides as inhibitors to CA isozymes limits their use. In this paper we have represented "Three Dimensional Quantitative Structure Activity Relationship" study to characterize structural features of Sulfamide derivative [RR'NSO(2)NH(2)] as inhibitors, that are required for selective binding of carbonic anhydrase isozymes (CAI and CAII). In the analysis, stepwise multiple linear regression was performed using physiochemical parameters as independent variable and CA-I and CA-II inhibitory activity as dependent variable, respectively. The best multiparametric QSAR model obtained for CA-I inhibitory activity shows good statistical significance (r= 0.9714) and predictability (Q(2)=0.8921), involving the Electronic descriptors viz. Highest Occupied Molecular Orbital, Lowest Unoccupied Molecular Orbital and Steric descriptors viz. Principal moment of Inertia at X axis. Similarly, CA-II inhibitory activity also shows good statistical significance (r=0.9644) and predictability (Q(2)=0.8699) involving aforementioned descriptors. The predictive power of the model was successfully tested externally using a set of six compounds as test set for CA-I inhibitory activity and a set of seven compounds in case of CA-II inhibitory activity with good predictive squared correlation coefficient, r(2)(pred)=0.6016 and 0.7662, respectively. Overview of analysis favours substituents with high electronegativity and less bulk at R and R' positions of the parent nucleus, provides a basis to design new Sulfamide derivatives possessing potent and selective carbonic anhydrase-II inhibitory activity.
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PMID:Quantitative structure activity relationship studies of sulfamide derivatives as carbonic anhydrase inhibitor: as antiglaucoma agents. 1762 76

Brinzolamide is a white powder commercially formulated as a 1% ophthalmic suspension to reduce intraocular pressure (IOP). Pharmacologically, brinzolamide is a highly specific, non-competitive, reversible, and effective inhibitor of carbonic anhydrase II (CA-II), able to suppress formation of aqueous humor in the eye and thus to decrease IOP. Several clinical trials have evaluated its safety and the most commonly ocular adverse events are blurred vision (3%-8%), ocular discomfort (1.8%-5.9%), and eye pain (0.7%-4.0%). Brinzolamide has been introduced to treat ocular hypertension and primary open-angle glaucoma. In some clinical studies it has been estimated that brinzolamide reduced IOP by was about 18%. Brinzolamide can be added to beta-blockers and prostaglandins. In the latter combination, because prostaglandin derivatives improve the uveoscleral outflow but also increase the activity of CA in ciliary epithelium with a secondary increase in aqueous humor secretion, and slightly reduce the efficacy of prostaglandin analogues, theoretically topical CA inhibitors (CAI) decrease IOP by inhibiting CA-II, thus improving prostaglandin efficacy as well as lowering IOP. Brinzolamide could have a secondary possible effect on ocular flow too. Some clinical studies showed a mild improvement of ocular blood flow. Theoretically, CAI could give rise to metabolic acidosis, with secondary vasodilatation and improvement of blood flow. Systemic acidosis can occur in the setting of oral CAI therapy, and local acidosis within ocular tissues is theoretically possible with topical CAI therapy, with the potential for a local increase in ocular blood flow. In conclusion, topical CAI treatment has efficacy in IOP-lowering ranging from 15% to 20%. From published data, brinzolamide can be used as first-line medication, even if other medications have a higher efficacy, with few side effects and it is a good adjunctive treatment. In some type of glaucoma patients with a vascular dysregulation, topical CAI could have a double effect: reducing IOP and improving ocular blood flow.
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PMID:Brinzolamide ophthalmic suspension: a review of its pharmacology and use in the treatment of open angle glaucoma and ocular hypertension. 1966 49

Examination of the response of the retinal proteome to elevated intraocular pressure (IOP) and to the pharmacological normalization of IOP is crucial, in order to develop drugs with neuroptorective potential. We used a hereditary rat model of ocular hypertension to lower IOP with travaprost and dorzolamide applied topically on the eye surface, and examine changes of the retinal proteome. Our data demonstrate that elevated IOP causes alterations in the retinal protein profile, in particular in high-mobility-group-protein B1 (HMGB1), calmodulin, heat-shock-protein (HSP) 70 and carbonic anhydrase II expression. The changes of the retinal proteome by dorzolamide or travoprost are different and independent of the IOP lowering effect. This fact suggests that the eye drops exert a direct IOP-independent effect on retinal metabolism. Further investigations are required to elucidate the potential neuroprotective mechanisms signaled through changes of HMGB1, calmodulin, HSP70 and carbonic anhydrase II expression in glaucoma. The data may facilitate development of eye drops that exert neuroprotection through direct pharmacological effect.
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PMID:Regulation of retinal proteome by topical antiglaucomatous eye drops in an inherited glaucoma rat model. 2279 52


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