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.

Article Details

Citation
Copy to clipboard

Imanishi M, Tomishima Y, Itou S, Hamashima H, Nakajima Y, Washizuka K, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K

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.

J Med Chem. 2008 Mar 27;51(6):1925-44. doi: 10.1021/jm701324c. Epub 2008 Feb 29.

PubMed ID
18307290 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
IsoprenalineBeta-1 adrenergic receptorEC 50 (nM)0.084N/AN/ADetails
IsoprenalineBeta-3 adrenergic receptorEC 50 (nM)0.97N/AN/ADetails