Takako Okumura

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP4 Receptor Antagonist with Antihyperalgesic Properties

The prostaglandin (PG) EP4 receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP4 receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP4 or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP4 receptor antagonist, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl]ethyl}amino) carbonyl]-4-methylbenzenesulfonamide (CJ-023,423). In vitro, CJ-023,423 inhibits [3H]PGE2 binding to both human and rat EP4 receptors with Ki of 13 ± 4 and 20 ± 1 nM, respectively. CJ-023,423 is highly selective for the human EP4 receptor over other human prostanoid receptor subtypes. It also inhibits PGE2-evoked elevation in intracellular cAMP at the human and rat EP4 receptors with pA2 of 8.3 ± 0.03 and 8.2 ± 0.2 nM, respectively. In vivo, oral administration of CJ-023,423 significantly reduces thermal hyperalgesia induced by intraplantar injection of PGE2 (ED50 = 12.8 mg/kg). CJ-023,423 is also effective in models of acute and chronic inflammatory pain. CJ-023,423 significantly reduces mechanical hyperalgesia in the carrageenan model. Furthermore, CJ-023,423 significantly reverses complete Freunds adjuvant-induced chronic inflammatory pain response. Taken together, the present data indicate that CJ-023,423, a highly potent and selective antagonist of both human and rat EP4 receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP4 receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.

Novel imidazole compounds as a new series of potent, orally active inhibitors of 5-lipoxygenase

Replacement of the dihydroquinolinone pharmacophore of Zenecas ZD2138 by ionizable imidazolylphenyl moiety has lead to the discovery of a novel series of potent and orally active 5-lipoxygenase (5-LO) inhibitors. The synthesis and structure-activity relationship (SAR) of this series of compounds are described herein.

Effects of the selective EP4 antagonist, CJ‐023,423 on chronic inflammation and bone destruction in rat adjuvant‐induced arthritis

Prostaglandin E2 (PGE2) produced by cyclooxygenase (COX) is a potent pro‐inflammatory mediator. We have recently discovered CJ‐023,423, a highly selective antagonist of EP4 receptors, one of the PGE2 receptors. This agent is suitable for exploring the effects of blocking EP4 receptors following oral administration in rats. In this study, CJ‐023,423 was used in rats with adjuvant‐induced arthritis (AIA) to investigate the role of the EP4 receptor in chronic inflammation and bone destruction. These effects were compared with those of rofecoxib, a selective COX‐2 inhibitor. CJ‐023,423 had significant inhibitory effects on paw swelling, inflammatory biomarkers, synovial inflammation and bone destruction in AIA rats. In particular, the inhibitory effect on paw swelling in AIA rats was comparable to that of rofecoxib. These results suggest that PGE2 acting via the EP4 receptor is involved in the development of chronic inflammation and bone destruction, particularly with respect to oedema in AIA rats. This is the first study to confirm the in‐vivo effects of EP4 receptor blockade on inflammation and bone destruction in AIA rats with a small‐molecule compound.

Involvement of inflammation in severe post‐operative pain demonstrated by pre‐surgical and post‐surgical treatment with piroxicam and ketorolac

Objectives  Post‐operative pain is considered to involve inflammation caused by tissue injury. However, the mechanism and timing of the involvement of inflammation in the post‐operative pain remain complicated because they can vary among different types of surgery. In this study a rat incision model was used to investigate how inflammation induced by cyclooxygenases (COXs) is involved in severe post‐operative pain.

Abstract 893: Anticancer effect and mechanism of prostaglandin E2 receptor EP4 antagonist

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Molecular studies reveal that over-expression of cyclooxygenase-2 (COX-2) is a prominent feature of premalignant and malignant neoplasms. The increased COX-2-mediated prostaglandin-E2 (PGE2) production has a strong association with various cancers, by promoting cell survival, cell growth, migration, invasion, angiogenesis, and immunotolerance. The use of COX-2 selective inhibitors has shown promise in the prevention and treatment of various cancers, however, the chronic use of COX-2 inhibitors is associated with an increased risk of cardiovascular adverse effects. Therefore, there is an urgent need to further understanding of the downstream mechanisms by which PGE2 promotes tumorigenesis and more effective strategies for the treatment of cancer. There are four PGE2 receptors, i.e., EP1, EP2, EP3, and EP4, involved in the pharmacology of PGE2. Accumulating evidences suggest that EP4 is the responsible receptor for PGE2 / COX-2-mediated tumorigenic signals in cancer cells and cancer microenvironment. On the other hands, signals from other prostaglandin receptors, e.g. IP and EP1, are reported to inhibit cancer proliferation or metastasis. These evidences suggest that selective blockade of EP4 would offer anti-cancer efficacy and safety advantages over COX-2 inhibition as cancer therapy. We have developed novel plural EP4 antagonists, with pA2 values of nanomolar range which are selective against other EP receptors. EP4 antagonists inhibited the PGE2-dependent productions of key molecules for cancer promotion i.e. VEGF, IL-23, and IL-6 in macrophages, dendritic cells, and PBMC, respectively. At the same time EP4 antagonist reversed PGE2 -induced TNFα and IL-12 suppression in human whole blood. As a consequence, EP4 antagonists exhibited anti-cancer activity in lung, GI, and prostate cancer models. These results indicate that selective EP4 antagonists show anti-cancer effect mediated by multifaceted mechanisms, and represent an attractive medicine for anti-cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 893. doi:1538-7445.AM2012-893