Uses
GW-311616 is a potent, orally bioavailable, long duration and selective human neutrophil elastase (HNE) inhibitor with IC50 value of 22 nM and Ki value of 0.31 nM[1].
in vivo
GW-311616 (2 mg/kg; oral administration) rapidly abolishes the circulation of neutrophil elastase (NE) in dogs, while >90% inhibition is maintained for 4 days. This prolonged effect is independent to be due to penetration of neutrophils in bone marrow by orally administrated GW-311616. GW-311616 has moderate terminal elimination half-life (t1/2) of 1.1 hours and 1.5 hours for dog (2 mg/kg, oral), rat (2 mg/kg, oral), respectively[3].
| Animal Model: | Dogs (9-month-old)[3] |
| Dosage: | 0.22 mg/kg, 0.66 mg/kg and 2 mg/kg (Pharmacokinetic study) |
| Administration: | Oral administration |
| Result: | At 0.22 mg/kg, greater than 50% inhibition of elastase was achieved 6 hours after dosing, with activity returning towards control values. Single oral dose of 2 mg/kg rapidly abolished circulating enzyme activity, and greater than 90% inhibition was maintained for 4 days.
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References
[1] Ohbayashi H,et al. Neutrophil elastase inhibitors as treatment for COPD. Expert Opin Investig Drugs. 2002 Jul;11(7):965-80. DOI:
10.1517/13543784.11.7.965[2] Jiang KL, et al. Neutrophil elastase and its therapeutic effect on leukemia cells. Mol Med Rep. 2015 Sep;12(3):4165-4172. DOI:
10.3892/mmr.2015.3946[3] Macdonald SJ, et al. The discovery of a potent, intracellular, orally bioavailable, long duration inhibitor of human neutrophil elastase--GW311616A a development candidate. Bioorg Med Chem Lett. 2001 Apr 9;11(7):895-8. DOI:
10.1016/s0960-894x(01)00078-6
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