Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and evaluation of physical properties as potential overactive bladder therapies: part 5.
As an extension of research conducted on beta(3)-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 beta(3)-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 EC(50) 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 beta(3) activity.
Chemistry Research Laboratories, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. kouji.hattori@jp.astellas.com
Kouji
K
Hattori
Susumu
S
Toda
Masashi
M
Imanishi
Shinji
S
Itou
Yutaka
Y
Nakajima
Kenichi
K
Washizuka
Takanobu
T
Araki
Hitoshi
H
Hamashima
Yasuyo
Y
Tomishima
Minoru
M
Sakurai
Shigeo
S
Matsui
Emiko
E
Imamura
Koji
K
Ueshima
Takao
T
Yamamoto
Nobuhiro
N
Yamamoto
Hirofumi
H
Ishikawa
Keiko
K
Nakano
Naoko
N
Unami
Kaori
K
Hamada
Yasuhiro
Y
Matsumura
Fujiko
F
Takamura
D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D055808:Drug Discovery; D005260:Female; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*
D058667:Adrenergic beta-3 Receptor Agonists; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; D000242:Cyclic AMP