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

Abstract

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) 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 alpha(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 alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) 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 alpha(1a) over the alpha(1b) and alpha(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.

Tumor anti-initiating activity of some novel 3, 4-dihydropyrimidinones

“…The IR spectra were recorded with a Philips Infracord Spectrophotometer Model PU9712 in KBr discs. 1 HNMR spectra were measured in CDCl 3 and DMSO-d 6 on JEOL-270 spectrometer with Me 4 Si as an internal standard. Mass spectra were obtained with a Shimadzu GCS-QP 1000 EX spectrometer at 70eV.…”

“…Cell protection from external damage largely depends on the availability and activity of cellular antioxidants, which maintain homeostatic control of ROS [4]. An altered balance of ROS directly affects cellular proliferation, apoptosis, and senescence [5].…”

“…The initiation phase is a rapid (within hours or days), irreversible event that occurs when a normal cell is exposed to a carcinogen that causes un-repairable or misrepaired DNA damage [5]. DNA damage itself is not mutagenic unless the resulting somatic mutation is recapitulated via mitosis to yield a clone of the mutated cell [4]. Because the initiation and progression phases are irreversible and relatively transient events, they may provide the best targets for cancer prevention [5].…”

“…Thus, in addition to their characteristic properties as anti-hypertensives [19,26], these compounds show a broad range of biological effects, including anti-viral [12,21], anti-inflammatory [31], anti-bacterial [24] and anti-tumor [4,27] activities. The discovery of monastrol, 4-(3-hydroxyphenyl)-6-methyl-5-ethylcarboxy-2-thioxo-1,2,3,4-tetrahydropyrimidine, as a mitotic kinesin Eg5 motor protein inhibitor [7], encouraged the search for and development of more anticancer compounds from the dihydropyrimidinone series.…”

Evaluation of the in vitro antiretroviral potential of some Biginelli-type pyrimidines

“…Aft er nine decades of being ignored, the pharmacological properties of this interesting heterocyclic scaff old attracted worthwhile attention of medicinal chemists (Kappe, 2000). Since the early 1980s, a broad range of biological eff ects, including calcium channel modulation (Rovnyak et al, 1992), adrenoceptor blocking activity (Barrow et al, 2000), antitumor (Klein et al, 2007), antibacterial (Ashok et al, 2007), antioxidant (Stefani et al, 2006) and anti-infl ammatory (Bahekar and Shinde, 2004) activities has been ascribed to this class of heterocycles. DHPMs also possess antiviral activity (Hurst and Hull, 1961).…”