2-MeS-β,γ-CCl2-ATP is a Potent Agent for Reducing Intraocular Pressure

• Published in: Journal of medicinal chemistry 2010-04, Vol.53 (8), p.3305-3319
• Main Authors: Eliahu, Shay, Martín-Gil, Alba, Perez de Lara, María Jesús, Pintor, Jesús, Camden, Jean, Weisman, Gary A, Lecka, Joanna, Sévigny, Jean, Fischer, Bilha
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - analogs & derivatives; Adenosine Diphosphate - chemical synthesis; Adenosine Diphosphate - pharmacology; Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - chemical synthesis; Adenosine Triphosphate - pharmacology; Animals; Cell Line, Tumor; Drug Stability; Humans; Hydrolysis; Intraocular Pressure - drug effects; Male; Purinergic P2 Receptor Agonists; Rabbits; Receptors, Purinergic P2Y1; Structure-Activity Relationship; Turkey
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100030u

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 °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 P2Y1 receptor (EC50 0.57−9.54 μM). Ocular administration of most analogues into rabbits reduced IOP, e.g., analogue 9 reduced IOP by 32% (EC50 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.