Indanesulfonamides as carbonic anhydrase inhibitors. Toward structure-based design of selective inhibitors of the tumor-associated isozyme CA IX.

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Thiry A, Ledecq M, Cecchi A, Dogne JM, Wouters J, Supuran CT, Masereel B

Indanesulfonamides as carbonic anhydrase inhibitors. Toward structure-based design of selective inhibitors of the tumor-associated isozyme CA IX.

J Med Chem. 2006 May 4;49(9):2743-9.

PubMed ID

16640335 [ View in PubMed

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Abstract

Carbonic anhydrases are ubiquitous metalloenzymes which are involved in fundamental processes (i.e., acid-base regulation, respiration, calcification, etc.). The carbonic anhydrase isozyme IX becomes an interesting pharmacological target due to its overexpression in cancer and its absence in normal tissue. Therefore, several indanesulfonamides were synthesized and tested for their inhibition both against the human CA IX and against two other biologically relevant isozymes (CA I and II). Structure-activity relationships are discussed and point out different compounds for its selectivity and activity against CA IX. To establish preliminary hypothesis for the design of new isozyme-selective CA IX inhibitors, we conducted molecular modeling. We describe here the first human CA IX model built by homology with another CA isozyme already crystallized. Docking studies were performed to explore the binding mode of our indanesulfonamide derivatives.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Acetazolamide	Carbonic anhydrase 1	Ki (nM)	900	7.5	22	Details
Acetazolamide	Carbonic anhydrase 2	Ki (nM)	12	7.5	22	Details