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Muralitharan Kengatharan, Barbara M. Wirostko, H Umeno, Henry H. Hsu; Pharmaceutical Profile Of A Novel Rho Kinase (ROCK) Inhibitor ATS907 For Reduction Of IOP In Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3106.
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To investigate the pharmaceutical profile of ATS907, studies were conducted to evaluate potency and selectivity, cell permeability, absorption and metabolism.
Standard protocols were used to assess: (i) kinase inhibitor profile of ATS907 (parent) and its primary metabolite, ATS907M1, against 18 kinases in isolated enzymes in vitro; (ii) cell permeability in caco-2 cells in vitro; (iii) generation of ATS907M1 in S9 fraction of liver homogenates from human (H), cynomolgus monkeys (NHP), dogs, and Japanese white rabbit (JWR) using LC-MS; and (iv) pharmacokinetic profile of ATS907 and ATS907M1 in aqueous humor following topical administration to rabbits.
The Ki (in nM) of ATS907 (parent) and ATS907M1 (metabolite) on ROCK1 was 36.0 and 7.8, and on ROCK2 was, 37.0 and 7.5 nM, respectively. Against other 16 kinases, ATS907 was less potent (i.e. >10X relative to ROCK in terms of IC50) in all but 2 kinases (relative potencies vs ROCK in terms of IC50 were PKA,4.5X; PKC theta, 4.0X). ATS907M1 was selective against the 16 kinases (relative potency vs ROCK >100X in terms of IC50). The major metabolite in the S9 fraction from livers of H, NHP and JWR was ATS907M1, while M1 was largely absent in dogs. Metabolism profile of H and NHP were comparable. In JWR, a larger quantity of ATS907M1 was observed. Cell permeability (x10E-6 cm/sec) of ATS907 was 38.2 and of ATS907M1 was 9.8. Following topical dosing in JWR, aqueous levels of both ATS907 and ATS907M1 reached Tmax within 1 hour, reflecting rapid penetration into the anterior chamber. ATS907 declined rapidly in the aqueous while ATS907M1 declined more slowly over 8 hrs. Plasma levels of metabolite were low and the parent ATS907 was undetectable.
Following topical administration, ATS907 is rapidly converted to a more potent and selective metabolite, ATS907M1. The rapid cellular penetration and conversion of the parent to ATS907M1 may offer advantages in providing a wider therapeutic index. This unique pro drug-like property of ATS907 makes it an attractive IOP lowering agent.
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