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).
AskAt Inc., 4F Ito Bldg., 4-11-28 Meieki Nakamura-ku, Nagoya 450-0002, Japan. Electronic address: yoshiyuki.okumura@askat.co.jp.
Yoshiyuki
Y
Okumura
Discovery Research, RaQualia Pharma Inc, 8F Daiwa Meieki Bldg., 1-21-19 Meieki Minami, Nakamura-ku, Nagoya 450-0003, Japan.
Tatsuya
T
Yamagishi
INC Research, 16F Shinagawa East One Tower, 2-16-1 Konan, Minato-ku, Tokyo 108-0075, Japan.
Seiji
S
Nukui
Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
Kazunari
K
Nakao
D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C000621941:AAT-008; D001565:Benzoates; D011448:Prostaglandin Antagonists; D058309:Receptors, Prostaglandin E, EP4 Subtype; D009536:Niacinamide
Autoimmune diseases; Cancer; Clinical candidate; EP4 receptor antagonist; Inflammation; Pain; Prostaglandin E2; Structure–activity relationship (SAR)