CE-224535 is a potent, highly selective, orally bioavailable, non-competitive antagonist of the human P2X7 receptor. Pre-clinical pharmacokinetic studies with CE-224535 indicate limited CNS penetration. In clinical trials, CE-224535 failed to demonstrate efficacy in a 2-week study of knee pain in osteoarthritis or a 12-week study in patients with rheumatoid arthritis. CE-224535 is safe and well tolerated after administration of up to 1600 mg as a single dose or 600 mg every 12 hours for 14 days in healthy subjects and 500 mg every 12 hours for 2 weeks in subjects with osteoarthritis of the knee and 12 weeks in rheumatoid arthritis patients with an inadequate response to methotrexate.