Update on carbonic anhydrase inhibitors: a patent review (2008 - 2011)

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.

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.

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.