CG100649, a novel dual-acting COX-2 and carbonic anhydrase inhibitor: Preclinical pharmacology

CG100649 is a novel dual-acting cyclooxygenase-2 (COX-2) and carbonic anhydrase (CA) inhibitor which is being developed for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. CG100649 has moderate COX-2 selectivity over COX-1, ranging from 15-fold in human cells (whole blood, platelets and macrophages) to 45-fold in mouse peritoneal macrophages. In the ex vivo COX-1 activity assay, CG100649 showed weaker COX-1 inhibitory activity than indomethacin in rat whole blood. CG100649 was a potent inhibitor of inflammation in adjuvant-induced arthritis and collagen-induced arthritis in Lewis rats (paw swelling ED50s were 0.10 and 0.22 mg/kg/day, respectively). CG100649 and indomethacin showed similar potencies in the mouse acute air pouch and rat acute paw edema inflammatory animal models. CG100649 was 5x more potent than indomethacin in the thermal hyperalgesia rat model and had significantly greater anti-pyretic potency than ibuprofen. CG100649 inhibited hCA I and II activity with IC50s of 0.336 µM and 0.062 µM, respectively (acetazolamide IC50s were 0.68 µM and 0.0091 µM, respectively). The CA inhibitory activity of CG100649 is unlikely to affect CG100649's intended therapeutic effects since CG100649 is believed to dissociate from CA and increase its local concentration in tissues which have low CA activity, such as inflamed joints. Given that CAs are abundantly present in a variety of tissues and cells, the high affinity of CG100649 for CAs may significantly affect the tissue distribution profile. CG100649 is expected to show reduced COX-2 inhibition in tissues or cells highly enriched with CAs (GI tract, blood, and kidney) due to substantial uptake of CG100649 by CAs; this may provide protection for organs of toxicity concern for NSAIDs. It is possible that the high affinity of CG100649 for CA could produce a reduction in blood pressure similar to the potent CA inhibitor acetazolamide. CG100649 is currently in phase II clinical trials in Europe.