Design and Synthesis of Novel α1a Adrenoceptor-Selective Dihydropyridine Antagonists for the Treatment of Benign Prostatic Hyperplasia
| Autor: | Dhanapalan Nagarathnam, Terry W. Schorn, Wai C. Wong, John M. Wetzel, Carlos Forray, Raymond S.L. Chang, William E. Heydorn, George Chiu, Theodore P. Broten, C. Gluchowski, Xingfang Hong, T. A. Branchek, Shou Wu Miao, James Fang, Mohammad R. Marzabadi |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Dihydropyridines medicine.medical_specialty Drug Evaluation Preclinical Prostatic Hyperplasia Nitro compound Blood Pressure In Vitro Techniques Pharmacology Binding Competitive Chemical synthesis Cell Line Structure-Activity Relationship Dogs Piperidines Prostate In vivo Receptors Adrenergic alpha-1 Internal medicine Drug Discovery medicine Animals Humans Adrenergic alpha-Antagonists chemistry.chemical_classification Chemistry Dihydropyridine Antagonist Muscle Smooth Stereoisomerism Hyperplasia medicine.disease Recombinant Proteins In vitro Rats medicine.anatomical_structure Endocrinology Adrenergic alpha-1 Receptor Antagonists Molecular Medicine Muscle Contraction medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 41:5320-5333 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We report the synthesis and evaluation of novel alpha1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha1a adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha1 antagonists such as prazosin and terazosin, with fewer side effects. |
| Databáze: | OpenAIRE |
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