Discovery of a Novel Series of Biphenyl Benzoic Acid Derivatives as Potent and Selective Human β3-Adrenergic Receptor Agonists with Good Oral Bioavailability. Part I
| Autor: | Masashi, Imanishi, Yasuyo, Tomishima, Shinji, Itou, Hitoshi, Hamashima, Yutaka, Nakajima, Kenichi, Washizuka, Minoru, Sakurai, Shigeo, Matsui, Emiko, Imamura, Koji, Ueshima, Takao, Yamamoto, Nobuhiro, Yamamoto, Hirofumi, Ishikawa, Keiko, Nakano, Naoko, Unami, Kaori, Hamada, Yasuhiro, Matsumura, Fujiko, Takamura, Kouji, Hattori |
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| Rok vydání: | 2008 |
| Předmět: |
Time Factors
Molecular Structure Biphenyl Compounds Drug Evaluation Preclinical Administration Oral Biological Availability Adrenergic beta-3 Receptor Agonists Blood Pressure Stereoisomerism Adrenergic beta-Agonists Benzoates Structure-Activity Relationship Dogs Drug Design Injections Intravenous Models Animal Drug Discovery Animals Humans Molecular Medicine Anesthesia Carbachol Female |
| Zdroj: | Journal of Medicinal Chemistry. 51:1925-1944 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm701324c |
| Popis: | A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists. |
| Databáze: | OpenAIRE |
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