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

Kenichi Saito,Katsuhiko Sakurada,Masakazu Komatsu,Tomohito Kozaki,Yukiko Endo,Hirotomo Shimizu,Hiroshi Kuriyama,Kosuke Tanaka,Junji Nakamura,Motoshi Shoda,Mineko Takeda,Akitoshi Ito

doi:10.1124/jpet.118.255034

Kenichi Saito, Katsuhiko Sakurada + Show 10 more

Open Access

https://doi.org/10.1124/jpet.118.255034

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Abstract

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.

Highlights

Phospholipase A2 (PLA2) enzymes recognize the sn-2 acyl bond of glycerophospholipids and hydrolyze the bond
AK106001616 inhibited rat cytosolic phospholipase A2 (cPLA2) with an IC50 value of 4.3 nmol/l (Fig. 2B), which is the IC50 value almost identical to that of human cPLA2
AK106-001616 inhibited cPLA2, and no difference between humans and rats was observed in its enzyme inhibitory activity

Summary

Introduction

Phospholipase A2 (PLA2) enzymes recognize the sn-2 acyl bond of glycerophospholipids and hydrolyze the bond. ABBREVIATIONS: AA, arachidonic acid; AIA, adjuvant-induced arthritis; AK106-001616, 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]-propionic acid; A23187, 5-(methylamino)-2-[[(2S,3R,5R,8S,9S)-3,5,9-trimethyl-2-[1-oxo-1-(1H-pyrrol-2-yl)propan-2-yl]-1,7-dioxaspiro[5.5]undecan8-yl]methyl]-1,3-benzoxazole-4-carboxylic acid; CAIA, collagen antibody-induced arthritis; CCI, chronic constriction injury; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; CV, cardiovascular; GI, gastrointestinal; IPF, idiopathic pulmonary fibrosis; iPLA2b, independent phospholipase A2b; LOX, lipoxygenase; LPS, lipopolysaccharide; LT, leukotriene; LTB4, leukotriene B4; LTE4, leukotriene E4; MC, methyl cellulose; NSAID, nonsteroidal antiinflammatory drug; OA, osteoarthritis; PAF, platelet-activating factor; PBMC, peripheral blood mononuclear cell; PG, prostaglandin; PGE2, prostaglandin E2; PGEM, prostaglandin E metabolite; PGF1a, prostaglandin F1a; PGI2, prostaglandin I2; PLA2, phospholipase A2; RA, rheumatoid arthritis; RBL-2H3, rat basophilic leukemia 2H3; SD, Sprague-Dawley; sPLA2, secretory phospholipase A2; tNSAID, traditional nonsteroidal anti-inflammatory drug; TXA2, thromboxane A2; TXB2, thromboxane B2. The use of tNSAIDs/COX-2 inhibitors has a small benefit in relieving symptoms for patients with RA (Allen et al, 2018) For these reasons there has been focused research into alternative targets that improve the efficacy and safety of anti-inflammatory drugs.

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