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Abstract #25658 Published in IGR 12-2
2-MeS-(beta),(gamma)-CCl(2)-ATP is a potent agent for reducing intraocular pressure
Eliahu S; Martin-Gil A; Perez De Lara MJ; Pintor J; Camden J; Weisman GA; Lecka J; Sevigny J; Fischer BJournal of Medicinal Chemistry 2010; 53: 3305-3319
Extracellular nucleotides can modify the production or drainage of the aqueous humor via activation of P2 receptors and therefore affect the intraocular pressure (IOP). We have synthesized slowly hydrolyzable nucleoside di- and triphosphate analogues, 1, and 8-14. Analogues 8-14 were completely resistant to hydrolysis by alkaline phosphatase over 30 min at 37 (degrees)C. In human blood serum, analogues 8-14 exhibited high stability, e.g., analogues 9 and 10-14 were only 15% and 0% degraded after 24 h, respectively. Moreover, analogues 8-14 were highly stable at pH 1.4 (t(1/2) 1 h-30 days). Analogues 8-14 were agonists of the P2Y(1) receptor (EC(50) 0.57-9.54 (mu)M). Ocular administration of most analogues into rabbits reduced IOP, e.g., analogue 9 reduced IOP by 32% (EC(50) 95.5 nM). Analogue 9 was more effective at reducing IOP than several common glaucoma drugs and represents a promising alternative to timolol maleate, which cannot be used for the treatment of patients suffering from asthma or cardiac problems.
B. Fischer. Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel. bfischer@mail.biu.ac.il
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
