Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives
| Autor: | Kazuhiro Otsuki, Hiroshi Yamamoto, Haruto Kurata, Ai Hashimoto, Koji Shinozaki, Takeshi Matsushita, Takuya Seko, Yoshiyuki Yamaura, Tetsuya Sekiguchi, Kensuke Kusumi, Akito Kakuuchi, Atsushi Naganawa |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pyrrolidines Stereochemistry Carboxylic acid Clinical Biochemistry Drug Evaluation Preclinical Administration Oral Biological Availability Pharmaceutical Science Biochemistry Pyrrolidine Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Dogs 0302 clinical medicine Drug Discovery Benzene Derivatives Animals Sphingosine-1-Phosphate Receptors Molecular Biology Alkyl chemistry.chemical_classification Organic Chemistry Chemical modification Haplorhini Combinatorial chemistry Rats Bioavailability Ring size Receptors Lysosphingolipid 030104 developmental biology chemistry 030220 oncology & carcinogenesis Urea Molecular Medicine Derivative (chemistry) Half-Life |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:1209-1213 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2016.01.031 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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