Adenosine Kinase Inhibitors. 6. Synthesis, Water Solubility, and Antinociceptive Activity of 5-Phenyl-7-(5-deoxy-β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidines Substituted at C4 with Glycinamides and Related Compounds

摘要: 4-(Phenylamino)-5-phenyl-7-(5-deoxy-β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (1) and related compounds known as “diaryltubercidin” analogues are potent inhibitors of adenosine kinase (AK) orally active in animal models pain such the rat formalin paw model (GP3269 ED50 = 6.4 mg/kg). However, utility this compound class is limited by poor water solubility that can be attributed to high energy crystallization caused stacking parallel C4 C5 aryl rings solid state (compound 1 GP3269 each with pH 7.4 <0.05 μg/mL). To increase solubility, hydrophobic C4-phenylamino substituent was replaced a more hydrophilic group, glycinamide. This modification resulted improved while retaining AK inhibition potency. Analogues were studied where changes glycinamide moiety combined base sugar. A lead compound, 4-N-(N-cyclopropylcarbamoylmethyl)amino-5-phenyl-7-(5-deoxy-β-d-ribofuranosyl)pyrrolo...