I am a
Home I AM A Search Login

Papers of the Week

2019 Jun

J Pharmacol Exp Ther



AK106-001616, a potent and selective inhibitor of cytosolic phospholipase A2: in vivo efficacy for inflammation, neuropathic pain, and pulmonary fibrosis.


Shimizu H, Ito A, Sakurada K, Nakamura J, Tanaka K, Komatsu M, Takeda M, Saito K, Endo Y, Kozaki T, Shoda M, Kuriyama H
J Pharmacol Exp Ther. 2019 Jun; 369(3):511-522.
PMID: 30971478.


AK106-001616 is a novel, potent, and selective inhibitor of the cytosolic phospholipase A2 (cPLA2) enzyme. Unlike traditional non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors, AK106-001616 reduced prostaglandin (PG) E2 and leukotriene (LT) B4 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 Emax 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 LTs 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, did not increase blood pressure, and did not increase the thromboxane A2/PGI2 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. SIGNIFICANCE STATEMENT: Idiopathic pulmonary fibrosis is a progressive and fatal interstitial disorder of the lung parenchyma. In 2014, pirfenidone and nintedanib were approved for the treatment of idiopathic pulmonary fibrosis. Although both drugs reduced the progression of idiopathic pulmonary fibrosis and offered survival benefits, no pharmacologic intervention is strongly recommended for patients with idiopathic pulmonary fibrosis. We conducted a medicinal chemistry-directed search for efficient therapeutic strategies and discovered AK106-001616 [3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)-phenyl]-propionic acid], a novel selective cPLA2 inhibitor. Herein, we describe the preclinical pharmacology of AK106-001616. We believe that readers of The Journal of Pharmacology and Experimental Therapeutics will be interested in this manuscript because our data demonstrate that oral AK106-001616 may provide valuable effects for wide indications without attendant gastrointestinal and cardiovascular risks.