Discovery of AAT-008, a novel,potent, and selective prostaglandin EP4 receptor antagonist |
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| Authors: | Yoshiyuki Okumura Tatsuya Yamagishi Seiji Nukui Kazunari Nakao |
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| Institution: | 1. AskAt Inc., 4F Ito Bldg., 4-11-28 Meieki Nakamura-ku, Nagoya 450-0002, Japan;2. Discovery Research, RaQualia Pharma Inc, 8F Daiwa Meieki Bldg., 1-21-19 Meieki Minami, Nakamura-ku, Nagoya 450-0003, Japan;3. INC Research, 16F Shinagawa East One Tower, 2-16-1 Konan, Minato-ku, Tokyo 108-0075, Japan;4. Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan |
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| Abstract: | 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). |
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| Keywords: | EP4 receptor antagonist Structure–activity relationship (SAR) Prostaglandin E2 Inflammation Pain Autoimmune diseases Cancer Clinical candidate |
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