- 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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- Oxazolidinones as alpha 1A receptor antagonists
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This invention is directed to oxazolidinone compounds which are selective antagonists for human alpha 1A receptors. 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 the antagonism of the alpha 1A receptor 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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- Phenylacetamides as selective α-1A adrenergic receptor antagonists
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A novel class of potent and selective α-1a receptor antagonists has been identified. The structures of these antagonists were derived from truncating the 4-aryl dihydropyridine subunit present in known α-1a antagonists. The design principles which led to the discovery of substituted phenylacetamides, the synthesis and SAR of key analogues, and the results of select in vitro and in vivo studies are described. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Patane, Michael A.,DiPardo, Robert M.,Newton, Randall C.,Price, RoseAnn P.,Broten, Theodore P.,Chang, Raymond S.L.,Ransom, Richard W.,Di Salvo, Jerry,Nagarathnam, Dhanapalan,Forray, Carlos,Gluchowski, Charles,Bock, Mark G.
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p. 1621 - 1624
(2007/10/03)
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- Design and synthesis of novel α1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia
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We report the synthesis and evaluation of novel ttia 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 α1a 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, DBF), with a DBF 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 aia adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective 0.1 antagonists such as prazosin and terazosin, with fewer side effects.
- Nagarathnam, Dhanapalan,Wetzel, John M.,Miao, Shou Wu,Marzabadi, Mohammad R.,Chiu, George,Wong, Wai C.,Hong, Xingfang,Fang, James,Forray, Carlos,Branchek, Theresa A.,Heydorn, William E.,Chang, Raymond S. L.,Broten, Theodore,Schorn, Terry W.,Gluchowski, Charles
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p. 5320 - 5333
(2007/10/03)
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