Discovery of tetrahydropyrido[4,3-d]pyrimidine derivatives for the treatment of neuropathic pain

• Synthesis of tetrahydropyrido-pyrimidines.
• Acute nociceptive assays performed.
• Chronic constriction injury and partial sciatic nerve ligation models in animals were used.
• Quantification of ED50 for potential analogs determined.
• Mechanistic studies on inflammatory mediation, oxidative and nitrosative stress performed.

A series of tetrahydropyridopyrimidine derivatives were synthesized and evaluated for neurotoxicity and peripheral analgesic activity followed by assessment of antiallodynic and antihyperalgesic potential in two peripheral neuropathic pain models, the chronic constriction injury (CCI) and partial sciatic nerve ligation (PSNL). Compounds (4b and 4d) exhibiting promising efficacies in four behavioral assays of allodynia and hyperalgesia (spontaneous pain, tactile allodynia, cold allodynia and mechanical hyperalgesia) were quantified for their ED50 values (15.12–65.10 mg/kg). Studies carried out to assess the underlying mechanism revealed that the compounds suppressed the inflammatory component of the neuropathic pain and prevented oxidative and nitrosative stress.

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