Yoshiyuki 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.

Efficient and practical synthesis of both enantiomers of 3-phenylcyclopentanol derivatives

An efficient, multigram scale synthesis of the respective optical isomers of 3-(substituted-phenyl) cyclopentanols was achieved by a lipase-catalyzed transesterification (kinetic resolution) in organic medium. This enzymatic reaction proceeded with great efficiency as measured by chemical yield and enantioselectivity. The racemic cis-alcohol 3 was successfully resolved to yield (1R,3S)-acetate 7 and the corresponding (1S,3R)-alcohol 3. The utility of this procedure was demonstrated by the practical syntheses of the biologically active compounds. The (1R,3S)-acetate 7 and the (1S,3R)-alcohol 3 were converted into orally active 5-lipoxygenase inhibitors, respectively, without loss of optical purity.

Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist

Starting from acylsufonamide HTS hit 2, a novel series of para-N-acylaminomethylbenzoic acids was identified and developed as selective prostaglandin EP4 receptor antagonists. Structural modifications on lead compound 4a were explored with the aim of improving potency, physicochemical properties, and animal PK predictive of QD (once a day) dosing regimen in human. These efforts led to the discovery of the clinical candidate AAT-008 (4j), which exhibited significantly improved pharmacological profiles over grapiprant (1).

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