| Autor: |
Barrow, J. C., Nantermet, P. G., Selnick, H. G., Glass, K. L., Rittle, K. E., Gilbert, K. F., Steele, T. G., Homnick, C. F., Freidinger, R. M., Ransom, R. W., Kling, P., Reiss, D., Broten, T. P., Schorn, T. W., Chang, R. S. L., O'Malley, S. S., Olah, T. V., Ellis, J. D., Barrish, A., Kassahun, K., Leppert, P., Nagarathnam, D., Forray, C. |
| Zdroj: |
Journal of Medicinal Chemistry; July 13, 2000, Vol. 43 Issue: 14 p2703-2718, 16p |
| Abstrakt: |
α1 Adrenergic receptors mediate both vascular and lower urinary tract tone, and α1 receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the α1A receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective α1A receptor subtype antagonists. In receptor binding assays, these types of compounds generally display Ki values for the α1a receptor subtype <1 nM while being greater than 100-fold selective versus the α1b and α1d receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the α1a over the α1b and α1d receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system. |
| Databáze: |
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