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

Abstract

4-(Phenylamino)-5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine 1 and related compounds known as "diaryltubercidin" analogues are potent inhibitors of adenosine kinase (AK) and are orally active in animal models of pain such as the rat formalin paw model (GP3269 ED50= 6.4 mg/kg). However, the utility of this compound class is limited by poor water solubility that can be attributed to the high energy of crystallization caused by stacking of the parallel C4 and C5 aryl rings in the solid state (compound 1 and GP3269 each with pH 7.4 solubility <0.05 microg/mL). To increase water solubility, the hydrophobic C4-phenylamino substituent was replaced with a more hydrophilic group, glycinamide. This modification resulted in improved water solubility while retaining AK inhibition potency. Analogues were studied where changes in the glycinamide moiety were combined with changes to the base and sugar. A lead compound, 4-N-(N-cyclopropylcarbamoylmethyl)amino-5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (16c) (IC50= 3 nM and water solubility = 32 +/- 9 microg/mL at pH 7.4), was further characterized in biological assays. Compound 16c exhibited strong oral efficacy in the rat formalin paw model (ED50 of 2.5 mg/kg). In the most advanced assay, 16c was found to inhibit bradykinin-induced licking in marmoset monkeys with an ED50 estimated at 0.9 mg/kg without producing evidence of side effects such as ataxia, sedation, and emesis at this dose. However, lethal toxicity in the rat formalin paw model occurred with high doses of 16c, and further work on this series was discontinued.

Adenosine Kinase: Exploitation for Therapeutic Gain

“…Although drugs from this compound class showed strong oral efficacy in pain models in the rat and marmoset monkey (ED 50 estimated at 0.9 mg/kg) without evidence of side effects such as ataxia, sedation, or emesis, one compound caused lethal toxicity in the rat formalin paw model. Therefore, work on this series of compounds was discontinued (Bookser et al, 2005b).…”

Steroidal pyrimidines: Synthesis, characterization, molecular docking studies with DNA and in vitro cytotoxicity

“…Furthermore, they possess anti-inflammatory [10] and analgesic activities which are well documented in the literature [11,12]. Besides this, pyrimidine derivatives have been explored for use as histamine and adenosine receptor antagonists as well as among several other biological receptors and modulators [13,14].…”

Synthesis, analgesic and anti-inflammatory activities evaluation of some bi-, tri- and tetracyclic condensed pyrimidines

“…Pyrimidine and condensed pyrimidines are important classes of heterocyclic compounds that exhibit a broad spectrum of biological activities such as anticancer [6][7][8][9][10], antiviral [11], antibacterial [12,13], antioxidant [14,15], anxiolytic [16] and antidepressant activities [17]. Furthermore, they possess anti-inflammatory [18][19][20][21][22][23][24] and analgesic activities that are well documented in the literature [25][26][27]. The bicyclic pyrrolo [1,2-c]pyrimidine derivative I [28] and the tricyclic pyrimido [5,4-e]pyrrolo [1,2-c]pyrimidines IIa, b [29] and III [30], prepared in our laboratory, were found to have significant analgesic and anti-inflammatory activities, therefore, in continuation of these efforts, we have been interested in the synthesis of further bi-, tri-, and tetracyclic condensed pyrimidine derivatives retaining the pyrrolo [1,2-c]pyrimidine as a basic nucleus and evaluating their analgesic and anti-inflammatory activities.…”