Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model.

BAY 41-4109 is a member of a class of heteroaryl-pyrimidines that was recently identified as potent inhibitors of human hepatitis B virus (HBV) replication. We have investigated the antiviral activity of BAY 41-4109 (methyl (R)-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-pyrimidine-5-carboxylate) in HBV-transgenic mice (Tg [HBV1.3 fsX(-)3'5']). Bay 41-4109 was administered per os using different schedules (b.i.d. or t.i.d. for up to 28 days) and dosages ranging from 3 to 30 mg/kg. The compound reduced viral DNA in the liver and in the plasma dose-dependently with efficacy comparable to 3TC. In contrast to 3TC-treated mice, we found a reduction of cytoplasmic hepatitis B virus core antigen (HBcAg) in liver sections of BAY 41-4109-treated mice, which indicated a different mode of action. Pharmacokinetic studies in mice have shown rapid absorption, a bioavailability of 30% and dose-proportional plasma concentrations. We conclude that BAY 41-4109 is a new anti-HBV drug candidate.

Stereoselective Mukaiyama-Michael/Michael/Aldol Domino Cyclization as the Key Step in the Synthesis of Pentasubstituted Arenes: An Efficient Access to Highly Active Inhibitors of Cholesteryl Ester Transfer Protein (CETP).

Seemingly heartbreaking for a stereochemist, the one-step selective construction of a stereopentad and its prompt destruction by aromatization has been proven to be an efficient strategy for the synthesis of fivefold substituted, pharmacologically highly active arenes (see scheme).

A new type of Ca-channel modulation by a novel class of 1,4-dihydropyridines.

Both Ca-antagonistic as well as Ca-agonistic 1,4-dihydropyridines (DHPs) have become extremely important tools to investigate the role of Ca-channels under various physiological and pathophysiological conditions. While Ca-antagonists stabilize the inactivated state of the Ca-channel without influencing the voltage dependent open and closed times, Ca-agonists prolong the mean open time of the channel. We here report for the first time the effects of a novel DHP, BAY Y 5959, which modulates Ca-channel gating in a unique manner: It increases both the mean open time and the mean closed time of the Ca-channel by binding to the DHP receptor. This results in a reduced rate of Ca-current activation, an increased peak current, and a strongly prolonged tail current decay. All these effects are strongly voltage dependent. Therefore it depends on resting membrane potential and shape of the action potential whether and how the Ca-influx into the cell is influenced. This novel mode of action of BAY Y 5959 results in an interesting pharmacological profile: It has a strong positive inotropic effect in the heart without influencing vessel tone. Therefore the term Ca-promoter is suggested; it could become a new approach for the drug treatment of congestive heart failure.

Determination of the absolute configuration of the active amlodipine enantiomer as (-)-S: a correction.

The active (-) enantiomer of amlodipine was originally reported to have R configuration. This does not concur with other 1,4-dihydropyridines with known absolute configuration. This configuration has now been determined by X-ray structural analysis using (1S)-camphanic acid and (S)-2-methoxy-2-phenylethanol as chiral probes. Both determinations gave the S configuration for the amlodipine (-) enantiomer with the greater Ca-antagonistic activity.

Pharmacologic and radioligand binding studies of 1,4-dihydropyridines in rat cardiac and vascular preparations: stereoselectivity and voltage dependence of antagonist and activator interactions.

The pharmacologic and radioligand-binding properties of 1,4-dihydropyridines in an activator (Bay K 8644) and an antagonist (nifedipine) series were studied in rat tail artery, heart membrane, and neonatal rat ventricular myocytes. The S-enantiomers of the activator series contracted rat tail artery in the presence of 15 mM K+ (EC50 values of 10(-8) to 10(-5) M). (S)-Bay K 8644 (I) and its o-difluoromethoxy analog (III) were the most potent members of the activator series examined. The abilities of the activators to stimulate maximum tension response of the artery differed with structure; thus, the efficacy of (S)-Bay K 8644 was 70% that of the analog lacking the 3-carbomethoxy group. The R-enantiomers of the activator series and a series of achiral nifedipine analogs were inhibitory in the same tissue. The intact-cell binding assay revealed the binding affinities of 1,4-dihydropyridine antagonists in depolarized cells (50 mM K+) to be higher than those in polarized cells (5 mM K+). The ratio KD (polarized)/KD (depolarized) was 77 for nifedipine (IC50 = 5.4 x 10(-9) M) but was only 2.9 for the weak 3-methoxy nifedipine analog (IC50 = 4.8 x 10(-6) M); an approximately linear relationship exists between this ratio and the antagonist potency. In marked contrast, and in confirmation of previous work [Mol. Pharmacol. 35:541-552 (1989)], the binding affinities of activators were not significantly affected by membrane potential, regardless of potency. We conclude that the S-enantiomers of Bay K 8644 analogs are activators with different potency and efficacy and that the R-enantiomers are antagonists, that the binding of 1,4-dihydropyridine antagonists is voltage dependent, whereas binding of the activators is not, and that the voltage-dependence of binding of the antagonists is correlated with the potency of the antagonist.