Update on carbonic anhydrase inhibitors: a patent review (2008 - 2011).
BACKGROUND
Carbonic anhydrases (CA) are a family of zinc metalloenzymes (EC 4.2.1.1) found in all organisms, catalyzing the reversible reaction of CO(2) hydration to bicarbonate and a proton. CAs are involved in various physiological reactions including respiration, pH regulation, Na(+) retention, calcification, tumorigenesis, electrolyte secretion, gluconeogenesis, ureagenesis, and lipogenesis. Hence CA inhibitors (CAIs) have long been studied as various classes of systemic anticonvulsants, anti-obesity, anti-pain, anti-tumor and topically acting anti-glaucoma agents, and agents for treating altitude sickness. In addition, CA isozyme IX (CA IX) has been shown to play a critical role in cancer proliferation, with CA IX overexpression in certain types of cancers leading to its use as a biomarker for cancer diagnosis and prognosis.


METHODS
Recently, the structures of all the catalytic α-CAs have been determined and with better understanding of gene-based RNA interference (RNAi) therapy, many patents on CA have been filed in the past few years. More new inhibitors are being tested in various labs around the world, in pursuit of designing high-affinity compounds that bind to specific isozymes of CA, thereby reducing side effects caused by off-target binding. This is a review on the patents filed related to CAs during 2008 - 2011.


CONCLUSIONS
Structural knowledge regarding CA isozymes offers great opportunity to explore and design inhibitors that will specifically bind to CA IX, avoid off-target binding with other CA isozymes and thus reduce side effects. Various in silico and kinetic studies to test and characterize novel and preexisting inhibitors for isozyme specificity are currently being conducted. However, there remains a need for more research to be carried out to develop better and more specific CAIs with lesser off-target inhibition.
University of Florida, College of Medicine, Department of Biochemistry and Molecular Biology, 1600 SW Archer Rd, PO Box 100245, Gainesville, FL 32610, USA.
Mayank
M
Aggarwal
Robert
R
McKenna
D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D007880:Legislation, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D010330:Patents as Topic; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases