Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 4; pp. 1209 - 1213
• Main Authors: Kusumi, Kensuke, Shinozaki, Koji, Yamaura, Yoshiyuki, Hashimoto, Ai, Kurata, Haruto, Naganawa, Atsushi, Otsuki, Kazuhiro, Matsushita, Takeshi, Sekiguchi, Tetsuya, Kakuuchi, Akito, Yamamoto, Hiroshi, Seko, Takuya
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.02.2016
• Subjects: Administration, Oral; Animals; Antagonist; Benzene Derivatives - chemical synthesis; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacokinetics; Biological Availability; Dogs; Drug Evaluation, Preclinical; G protein-coupled receptors; Half-Life; Haplorhini; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacokinetics; Rats; Receptors, Lysosphingolipid - antagonists & inhibitors; Receptors, Lysosphingolipid - metabolism; Sphingosine-1-phosphate receptor 2; Structure-Activity Relationship; Sphingosine-1-phosphate receptor 2; WCDFXVWDGHHCSI-UHFFFAOYSA-N; G protein-coupled receptors; Antagonist
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.01.031

[Display omitted] The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.