AK106-001616, a Potent and Selective Inhibitor of Cytosolic Phospholipase A2: In Vivo Efficacy for Inflammation, Neuropathic Pain, and Pulmonary Fibrosis.


Laboratories for Pharmacology (H.S., A.I., Ka.S., J.N., K.T., M.K., M.T., Ke.S., Y.E., H.K.), Safety Assessment and ADME (T.K.), and Medicinal Chemistry (M.S.), Pharmaceuticals Research Center, Asahi Kasei Pharma Co. Ltd., Izunokuni, Shizuoka, Japan [Email]


3-[3-Amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)-phenyl]-propionic acid (AK106-001616) is a novel, potent, and selective inhibitor of the cytosolic phospholipase A2 (cPLA2) enzyme. Unlike traditional nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors, AK106-001616 reduced prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production by stimulated cells. The suppression of PGE2 and LTB4 production was also confirmed using an air pouch model in rats administered a single oral dose of AK106-001616. AK106-001616 alleviated paw swelling in a rat adjuvant-induced arthritis (AIA) model. The maximum effect of the inhibitory effect of AK106-001616 was comparable with that of naproxen on paw swelling in a rat AIA model. Meanwhile, the inhibitory effect of AK106-001616 was more effective than that of naproxen in the mouse collagen antibody-induced arthritis model with leukotrienes contributing to the pathogenesis. AK106-001616 dose dependently reversed the decrease in paw withdrawal threshold not only in rat carrageenan-induced hyperalgesia, but also in a rat neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI). However, naproxen and celecoxib did not reverse the decrease in the paw withdrawal threshold in the CCI model. Furthermore, AK106-001616 reduced the disease score of bleomycin-induced lung fibrosis in rats. In addition, AK106-001616 did not enhance aspirin-induced gastric damage in fasted rats, increase blood pressure, or increase the thromboxane A2/ prostaglandin I2 ratio that is thought to be an underlying mechanism of thrombotic cardiovascular events increased by selective cyclooxygenase-2 inhibitors. Taken together, these data demonstrate that oral AK106-001616 may provide valuable effects for wide indications without attendant gastrointestinal and cardiovascular risks.