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Muralitharan Kengatharan, Hiroshi Umeno, Barbara Wirostko, Henry Hsu; Pharmaceutical Profile of a Novel Rho Kinase (ROCK) inhibitor ATS8535 for Reduction of IOP in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5081.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the pharmaceutical profile of ATS8535, studies were conducted to evaluate potency and selectivity, cell permeability, absorption and metabolism.
Standard protocols were used to assess: (i) kinase inhibitor profile of ATS8535 (parent) and its primary metabolite, ATS8535M1, against 18 kinases in isolated enzymes in vitro; (ii) cell permeability in caco-2 cells in vitro; (iii) generation of ATS8535M1 in S9 fraction of liver homogenates from human (H), cynomolgus monkeys (NHP), dogs, Japanese white rabbit (JWR) using LC-MS; and (iv) pharmacokinetic profile of ATS8535 and ATS8535M1 in aqueous humor following topical administration to rabbits.
The IC50 (in nM) of ATS8535 (parent) and ATS8535M1 (metabolite) on ROCK1 was 520 and 71 and on ROCK2 was, 350 and 49, respectively. Against other 16 kinases, ATS8535 was less potent (i.e. >10X relative to ROCK1 in terms of IC50) in all but 2 kinases (relative potencies vs ROCK in terms of IC50 were PKA,4.7X; PKC theta, 5.7X). ATS8535M1 was selective against the 16 kinases (relative potency vs ROCK1 >100X in terms of IC50). The major metabolite of ATS8535 in the S9 fraction from livers of H, NHP and JWR was ATS8535M1, while M1 was largely absent in dogs. Metabolism profile of H and NHP were comparable. In JWR, a larger quantity of ATS8535M1 was observed. Cell permeability of ATS8535 was 30.29x10E-6 cm/sec which was similar to propranolol (high permeability). Following topical dosing of ATS8535 in JWR, aqueous levels of both ATS8535 and ATS8535M1 reached Tmax within 1 hour, reflecting rapid penetration into and the conversion within the anterior chamber. ATS8535 declined rapidly in the aqueous while ATS8535M1 declined more slowly over 8 hrs. Plasma levels of metabolite were low and the parent was undetectable.
Following topical administration, ATS8535 is rapidly converted to a more potent and selective metabolite, ATS8535M1. The rapid cellular penetration and conversion of the parent to ATS8535M1 may offer advantages in providing a wider therapeutic index. This unique prodrug-like property of ATS8535 makes it an attractive topical IOP lowering agent.
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