Discovery of Novel N-Phenylglycine Derivatives as Potent and Selective β3-Adrenoceptor Agonists for the Treatment of Frequent Urination and Urinary Incontinence
| Autor: | Hideyuki Rasukasasu Azumino Muranaka, Satoshi Akahane, Harunobu Mukaiyama, Hiroshi Miyata, Masuo Akahane, Nobuyuki Tanaka, Akihito Hirabayashi, Tetsuro Tamai |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Agonist medicine.drug_class Muscle Relaxation Urinary system Urinary Bladder Glycine Urination Blood Pressure Urinary incontinence In Vitro Techniques Pharmacology Frequent urination Structure-Activity Relationship Heart Rate Pregnancy Receptors Adrenergic beta Drug Discovery Pressure medicine Animals Potency Beta (finance) Chemistry Uterus Ferrets Muscle Smooth Adrenergic beta-Agonists Rats Urinary Incontinence Muscle relaxation Receptors Adrenergic beta-3 Ritodrine Molecular Medicine Female medicine.symptom medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 44:1436-1445 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm000455z |
| Popis: | With a novel assay using isolated ferret detrusor to estimate beta(3)-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta(2)-adrenoceptor agonist, are potent beta(3)-adrenoceptor agonists, with excellent selectivity versus beta(1) and beta(2) subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the beta(3)-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f-i exhibited potent beta(3)-adrenoceptor-mediated relaxation of ferret detrusor (EC(50) = 0.93, 11, 14, and 160 nM) and higher potency at beta(3)-adrenoceptors than at beta(1) or beta(2). The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED(50) = 48 microg/kg) without cardiovascular side effects. This article is the first report of structure-activity relationships (SAR) concerning beta(3)-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence. |
| Databáze: | OpenAIRE |
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