A Novel Class of Orally Active Non-Peptide Bradykinin B2 Receptor Antagonists. 2. Overcoming the Species Difference between Guinea Pig and Man
| Autor: | Hirokazu Tanaka, Noriaki Inamura, Chie Hatori, Yoshito Abe, Masayuki Asano, Takayuki Inoue, Hiroe Sawai, Yuki Sawada, Hiroshi Kayakiri, Teruo Oku, Shigeki Satoh |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Receptor Bradykinin B2 Pyridines Bronchoconstriction Guinea Pigs Drug Evaluation Preclinical Administration Oral Bradykinin Pharmacology Cell Line Guinea pig Structure-Activity Relationship chemistry.chemical_compound Species Specificity Ileum Oral administration In vivo Drug Discovery Animals Humans Receptor Bradykinin Receptor Antagonists Bradykinin B2 Receptor Antagonists Receptors Bradykinin Anti-Inflammatory Agents Non-Steroidal Antagonist chemistry Biochemistry Epidermoid carcinoma Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 41:4053-4061 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Recently we reported the identification of a series of 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridines as the first orally active non-peptide bradykinin (BK) B2 receptor antagonists (1-3). These compounds inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors with nanomolar IC50's and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea pigs at 1 mg/kg by oral administration. However, it was found that their affinities for the B2 receptors in human A-431 cells (human epidermoid carcinoma) were much lower. Intensive modifications of the terminal substituents at the glycine moiety elucidated the structure-activity relationships (SAR) for human B2 receptors, leading to an extended basic framework which incorporated a novel key pharmacophore. Thus, we overcame the species difference and identified the first clinical candidate 18c (FR167344) with IC50's of 0.66 and 1.4 nM for guinea pig ileum and human A-431 cells, respectively. This compound displayed in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.17 mg/kg by oral administration. This novel non-peptide B2 antagonist is extremely potent both in vitro and in vivo by oral administration and is expected to be the first member of a new class of drug for the treatment of various inflammatory diseases. |
| Databáze: | OpenAIRE |
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