Discovery of Highly Potent and Selective Biphenylacylsulfonamide-Based β3-Adrenergic Receptor Agonists and Evaluation of Physical Properties as Potential Overactive Bladder Therapies:
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- 作者：Kouji Hattori ; Susumu Toda ; Masashi Imanishi ; Shinji Itou ; Yutaka Nakajima ; Kenichi Washizuka ; Takanobu Araki ; Hitoshi Hamashima ; Yasuyo Tomishima ; Minoru Sakurai ; Shigeo Matsui ; Emiko Imamura ; Koji U
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：May 14, 2009
- 年：2009
- 卷：52
- 期：9
- 页码：3063-3072
- 全文大小：201K
- 年卷期：v.52,no.9(May 14, 2009)
- ISSN：1520-4804
文摘
As an extension of research conducted on β3-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human β3-AR agonists with improved oral bioavailability compared to the previous series. Results of structure−activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC50 values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve β3 activity.