- 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines
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This invention is directed to dihydropyrimidine compounds of the following formula: which are selective antagonists for human α1Areceptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where antagonism of the α1Areceptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
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- Selective alpha1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones.
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A series of alpha1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in the low nanomolar to picomolar range along with high selectivity was obtained. In vivo efficacy in a prostate contraction model in rats was observed with a few derivatives.
- Nantermet,Barrow,Selnick,Homnick,Freidinger,Chang,O'Malley,Reiss,Broten,Ransom,Pettibone,Olah,Forray
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p. 1625 - 1628
(2007/10/03)
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- In vitro, and in vivo, evaluation of dihydropyrimidinone C-5 amides as potent and selective α(1A) receptor antagonists for the treatment of benign prostatic hyperplasia
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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 α(1A) 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 α(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the α(1a) receptor subtype 20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the α(1a) over the α(1b) and α(1d) 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.
- Barrow, James C.,Nantermet, Philippe G.,Selnick, Harold G.,Glass, Kristen L.,Rittle, Kenneth E.,Gilbert, Kevin F.,Steele, Thomas G.,Homnick, Carl F.,Freidinger, Roger M.,Ransom, Rick W.,Kling, Paul,Reiss, Duane,Broten, Theodore P.,Schorn, Terry W.,Chang, Raymond S. L.,O'Malley, Stacey S.,Olah, Timothy V.,Ellis, Joan D.,Barrish, Andrea,Kassahun, Kelem,Leppert, Paula,Nagarathnam, Dhanapalan,Forray, Carlos
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p. 2703 - 2718
(2007/10/03)
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