β3-Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropionic acid
| Autor: | Nobuyuki Tanaka, Akihito Hirabayashi, Masuo Akahane, Hideyuki Muranaka, Harunobu Mukaiyama, Takehiro Ishikawa, Satoshi Akahane, Tetsuro Tamai |
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| Rok vydání: | 2001 |
| Předmět: |
Detrusor muscle
Agonist Stereochemistry medicine.drug_class Carboxylic acid Clinical Biochemistry Drug Evaluation Preclinical Substituent Urination Pharmaceutical Science Adrenergic beta-3 Receptor Agonists Ether Biochemistry Frequent urination Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Phenols Heart Rate In vivo Drug Discovery medicine Animals Heart Atria Molecular Biology chemistry.chemical_classification Uterus Organic Chemistry Ferrets Adrenergic beta-Agonists Rats Urinary Incontinence medicine.anatomical_structure chemistry Molecular Medicine Female Propionates medicine.symptom |
| Zdroj: | Bioorganic & Medicinal Chemistry. 9:3265-3271 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/s0968-0896(01)00240-1 |
| Popis: | In a search for novel analogues of beta(3)-adrenoceptor (AR) agonists relaxing the bladder for treatment of urinary dysfunction, 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]-2-methylpropionic acids (1a-e), into which a fibrate-like structure had been incorporated, were synthesised. Compound 1a was found to be a selective beta(3)-AR agonist in functional assays using the ferret detrusor (beta(3)-AR), rat uterus (beta(2)-AR), and rat atrium (beta(1)-AR); beta(3): EC(50)=7.8 nM, beta(2): IC(50)=7,300 nM, beta(1): EC(20)=23,000 nM. The introduction of a chlorine atom or methyl substituent at the ortho-position on the phenyl ring of 1a further improved beta(3)-AR selectivity. In an in vivo study, 1a lowered intrabladder pressure (ED(50)=31 microg/kg) in rats, without increasing heart rate, in keeping with the in vitro results. Consequently, it is proposed that 1a and its analogues (1b-e), possess beta(3)-AR agonistic activity in the absence of undesirable beta(1)- or beta(2)-AR mediated actions, and may be useful for clinical treatment and pharmacological studies. |
| Databáze: | OpenAIRE |
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