You are on page 1of 2

BMCL PAPER Carbonic anhydrase (CA) inhibition has been demonstrated to r

educe fluid flow into the eye and alleviate high IOP.For over 40 years CA inhibi
tors (CAIs) were available only as pills, and these were intended for other ther
apies. These consisted of acetazolamide,
methazolamide, and dichlorphenamide. Although well tolerated by manypatients, th
ey are also associated with serious side effects such as weight loss, leucopenia
, and metabolic acidosis. To minimize the incidence and severity of adverse even
ts, topical ocular dosing of
CAIs was explored as alternative treatment for glaucoma. In 1995 Trusopt, the fi
rst eye drop for topical dosing was introduced, using dorzolamide as the CA inhi
bitor (CAI). Another CAI, brinzolamide, followed in 1998. The incidence of side
effects was lowered by local
versus systemic dosing, but adverse events still occur in some patients.
CA 2 07 R-Carbonic anhydrases (CAs) are ubiquitously distributed z
inc metalloenzymes that are implicated in a variety of physiological functions.
A total of 16 CA isozymes are presently known in humans: four are cytoplasmic (C
A I-III and VII) and two are mitochondrial (CA VA and VB), whereas others are se
creted (CA VI) or are membrane-bound (CA IV, IX, XII, and XIV).1 These enzymes c
atalyze the reversible hydration of CO2 to form HCO3-, which is involved in many
biosynthetic reactions, among which are gluconeogenesis, lipogenesis, the synth
esis of certain amino acids, and pyrimidine nucleotide biosynthesis. Moreover, t
hese enzymes are involved in pH homeostasis, bone resorption, ion transport, ele
ctrolyte secretion in a variety of tissues, calcification, and tumorigenesis. Th
us, it is not surprising that many of their isozymes have been discovered as imp
ortant targets for inhibitors with clinical applications. Several inhibitors of
human CAs have been utilized as antiglaucoma, anticonvulsant, aniurolithic, anti
epileptic, and anticancer agents. Most of these drugs (such as acetazolamide, me
thazolamide,or brinzolamide clinically used for the treatment of glaucoma) conta
in a sulfonamide group as an anchoring system to coordinate the catalytic zinc.
X-ray crystallographic structures are available for many adducts of sulfonamide
inhibitors with various CA isozymes. In all these complexes, the deprotonated su
lfonamide is coordinated to the Zn(II) ion and its NH moiety forms a hydrogen bo
nd with the Oç of Thr199, which in turn is engaged in another hydrogen bond with t
he carboxylate group of Glu106. Moreover, one of the SO2 oxygen atoms participat
es in a hydrogen bond with the backbone NH moiety of Thr199. Typically, a CA inh
ibitor must possess (i) a zinc-binding function (ZBF), such as sulfonamide, sulf
amate, hydroxamate, and so forth; (ii) an organic scaffold (usually an aromatic
or heterocyclic moiety); and (iii) a tail attached to the scaffold that increase
s solubility in water. Human CA II (hCA II) is the physiologically most relevant
and widespread CA isoform that has been most extensively studied from the struc
tural and inhibitor design points of view. This enzyme, together with hCA IV, is
involved in the pathogenesis of glaucoma, since it is present in the ciliary pr
ocess of the eye, where it is responsible for an increased secretion of bicarbon
ate and aqueous humor that causes an elevated intraocular pressure. CA II is pre
sent also in tissues other than that of the eye, such as the blood, kidneys, lun
gs, central nervous system, and so forth. The available pharmacological agents p
ossess many undesired side effects, mainly due to their lack of selectivity for
the different isozymes. Thus, development of isozyme-specific or at least organs
elective inhibitors would be highly beneficial. From a computational point of vi
ew, many 3D quantitative structure-activity relationship (QSAR) studies of CA in
hibitors have been developed, and furthermore, in 2001-2002, Gru¨neberg and co-wor
kers used a new pharmacophoredocking strategy for successfully virtual screening
novel CA II inhibitors.
2009 nejm glaucoma is a chronic, degenerative optic neuropathy that c
an be distinguished from most other forms of acquired optic neuropathy by the ch
aracteristic appearance of the optic nerve. In glaucoma, the neuroretinal rim of
the optic nerve becomes progressively thinner, thereby enlarging the optic-nerv
e cup. This phenomenon is referred to as optic-nerve cupping. Its cause is the l

TWMF7-M387V-XKW4Y-PVQQD-RK7C8 . 774GJ-X3942-9GTKT-FWYJ9-KM77K. the optic-nerve tissue loses its pink color and cupping does not deve lop. A rare exception is arteritic anterior ischemic optic neuropathy. In other optic neu ropathies.1 Patients with glaucoma typically lose peripheral vision and may lose all vision if not treated.oss of retinal ganglion cell axons. office 2010 key 2MHJR-V4MR2-V4W2Y-72MQ7-KC6XK. along with supporting glia and vasculature. in which cupping can occur. 4F 3B6-JTT3F-VDCD6-G7J4Q-74W3R win 7 ultimate SDER5-88KIG-NUI9E-22SPA-57LKM. The remaining neuroretinal rim retains its normal pink color.