Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I

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 investiga...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-03, Vol.51 (6), p.1925-1944
Main Authors: Imanishi, Masashi, Tomishima, Yasuyo, Itou, Shinji, Hamashima, Hitoshi, Nakajima, Yutaka, Washizuka, Kenichi, Sakurai, Minoru, Matsui, Shigeo, Imamura, Emiko, Ueshima, Koji, Yamamoto, Takao, Yamamoto, Nobuhiro, Ishikawa, Hirofumi, Nakano, Keiko, Unami, Naoko, Hamada, Kaori, Matsumura, Yasuhiro, Takamura, Fujiko, Hattori, Kouji
Format: Article
Language:English
Subjects:
Administration, Oral
Adrenergic beta-3 Receptor Agonists
Adrenergic beta-Agonists - chemical synthesis
Adrenergic beta-Agonists - chemistry
Adrenergic beta-Agonists - pharmacology
Anesthesia
Animals
Benzoates - chemical synthesis
Benzoates - chemistry
Benzoates - pharmacology
Biological Availability
Biphenyl Compounds - chemistry
Blood Pressure - drug effects
Carbachol - antagonists & inhibitors
Carbachol - pharmacology
Dogs
Drug Design
Drug Evaluation, Preclinical
Female
Humans
Injections, Intravenous
Models, Animal
Molecular Structure
Stereoisomerism
Structure-Activity Relationship
Time Factors
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Summary: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.
ISSN:0022-2623
DOI:10.1021/jm701324c