Carbonic anhydrase II inhibitors

Carbonic anhydrase II inhibitors, IC50 = 0.6 nM (left) and 0.8 nM (right)... 

Poulsen S-A, Bomaghi LF (2006) Fragment-based drug discovery of carbonic anhydrase II inhibitors by dynamic combinatorial chemistry utilizing cross metathesis. Bioorg Med Chem 14 3275-3284... 

Figure 12.8 Structure-based virtual screening examplesformiscellaneoustargets. (a) Carbonic anhydrase II inhibitors, IC50 0.6nM (left),...

K. A. Rossi, K.M.MerzJr.,G.M. Smith, and J.J. Baldwin,/. Med. Chem., 38,2061 (1995). Application of the Free Energy Perturbation Method to Human Carbonic Anhydrase II Inhibitors. 

The inhibition of carbonic anhydrase has been investigated by Merz and co-workers. In one study the relative binding free energies of the sulfonamide and sulfonate forms of an inhibitor, and the contribution of the hydrophobic hexyl tail of this inhibitor to binding, were both calculated. The later calculation is particularly difficult, and required several different approaches to achieve close agreement with the experimental data. In a more recent study, these authors demonstrated that FEP simulations on human carbonic anhydrase II inhibitors could predict energetic trends reasonably well, but these calculations were less successful in reproducing detailed structural data. 

Grtineberg S, Wendt B, Klebe G. Subnanomolar inhibitors from computer screening a model study using human carbonic anhydrase II. Angew Chem Int Ed Engl 2001 40 389-393 Angew Chem 2001 113 404-8. 

Figure 12. Oligoglycine-linked para-substituted benzenesulfonamides as inhibitors of carbonic anhydrase II.

Dorzolamide Hydrochloride is an inhibitor of human carbonic anhydrase II. The inhibition of carbonic anhydrase in the ciliary processes of the eye decreases the secretion of aqueous humor, with a resulting reduction in intraocular pressure. The drug is formulated as an ophthalmic solution, and administered topically as eyedrops. 

A series of 5-substituted thieno[2,3-. ]thiophene-2-sulfonamides 159-162 and 6,6-dioxidothieno[2,3- ]thiophene-2-sulfonamides 163-166 were prepared for evaluation as inhibitors of carbonic anhydrase II. Oxidation of 5-substituted thieno[2,3-. ]thiophene-2-sulfonamides provided the first examples of 6,6-dioxidothieno[2,3-3]thiophene-2-sulfona-mides. It was found that compounds with the more acidic SO2NH2 group showed higher activity for human carbonic... 

Figure 7.6 ESI of zinc metalloenzyme carbonic anhydrase, (a)-(c) under acidic denaturing conditions (d)-(f) native state conditions and (g) native state conditions with a specific inhibitor. Structure of entry (d) is Protein Data Bank ID IBN1. Boriack-Sjodin, P.A., Zeitlin, S., Chen, H.H., Crenshaw, L, Gross S., Dantanarayana, A., Delgado, P., May J.A., Dean, T., Christianson, D.W. Structural analysis of inhibitor binding to human carbonic anhydrase II. Protein Sciv 1998, 7, 2483-2489.

A practical application for the casting approach was demonstrated in 1997 by Lehn and Hue, who developed an inhibitor for carbonic anhydrase II (a zinc-based metalloenzyme responsible for the conversion of CO2 to HC03 and H+, cf. Section 11.3.2). The process is based on the Schiff base imine forming reaction of an aldehyde and an amine, a process which is reversible under physiological... 

Nasr G, Petit E, Supuran CT, Winum JY, Barboiu M (2009) Carbonic anhydrase II-induced selection of inhibitors from a dynamic combinatorial library of Schiff s bases. Bioorg Med Chem Lett 19 6014-6017... 

Figure 10 Inhibitors of carbonic anhydrase II. Compounds 9 and 10 are subnanomolar inhibitors identified through virtual screening. Compound 8 is the marketed drug dorzolamide.

J Gao, X Chen, R Chen, GB Sigal, JE Bruce, BL Schwartz, SA Hofstadler, GA Anderson, RD Smith, GM Whiteside. Screening derivatized peptide libraries for tight binding inhibitors to carbonic anhydrase II by electrospray ionization-mass spectrometry. J Med Chem 39 1949-1955, 1996. 

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