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Hiroyoshi Hidaka, Kengo Sumi, Takashi Izuhara, Atsuko Kasai, Hitomi Tanimoto; A novel isoquinoline sulfonamide protein kinase inhibitor (H-1337) produces long-lasting reduction of IOP. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5712.
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Isoquinoline sulfonamide derivatives have been known to inhibit selectively a variety of protein kinases (Hidaka et al., Biochemistry. 23: 5036-41, 1984, Hidaka et al., Methods Enzymol. 201: 328-339, 1991). Moreover, two of these inhibitors have been already succeeded to be used in the market for clinical therapies. We, here introduce another novel sulfonamide protein kinase inhibitor, H-1337, with potent IOP-lowering activity.
H-1337 (isoquinoline sulfonamide) was newly synthesized in our own laboratory and subjected to test for IOP-lowering activity and toxicological studies. Inhibition of the compound for various protein kinases were carried out by Cerep Corporation.
Leucine-rich repeat kinase 2 (LRRK2) was most effectively inhibited (IC50: 0.045 μM) by H-1337. Novel LRRK2-inhibitor (H-1337) was selected after extensive screening for protein kinase inhibition including LRRK2. The structure of H-1337 was born from our discovery (Hidaka et al., J Pharmacol Exp Ther. 207: 8-15, 1978) since about 40 years ago. Many of these isoquinoline sulfonamides are still now commercially available as chemical reagents such as H-7, H-8, H-9, H-89, KN-93, ML-7 and ML-9, etc. Potent (maximum reductions were 7.3 mmHg and 4.3 mmHg after administrations of 1% and 0.3% H-1337 in rabbits and cynomolgus monkeys, respectively) and long-lasting (durations were over 14 h and 24 h in rabbits and monkeys, respectively) IOP lowering and no systemic and no ocular toxicity was observed in animal models.
Inhibition of LRRK2 by H-1337 is unique character. Effective and long-lasting reduction of IOP by H-1337 could be explained by this specific kinase inhibition. (See our poster about the mechanism of IOP-lowering by H-1337, which is presented in detail by Kasai et al.)
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