Pharmacokinetics/pharmacodynamics of Y-700, a novel xanthine oxidase inhibitor, in rats and man.

The pharmacokinetics and pharmacodynamics of a novel xanthine oxidase (XO) inhibitor, Y-700, were evaluated in rats and healthy male volunteers. In a rat model of hyperuricemia, oral Y-700 (0.3-10 mg/kg) showed a more potent and a longer-lasting hypouricemic action than allopurinol. A single oral dosing of Y-700 (5, 20 or 80 mg) to volunteers caused a dose-dependent reduction of serum uric acid levels indicating close relationship to plasma concentrations of the compound. In addition, Y-700 was hardly excreted in urine but mainly excreted in feces in rats and volunteers. These results suggested that Y-700 is a new effective inhibitor of XO in rats and humans with high oral bioavailability being predominantly eliminated via the liver unlikely to allopurinol.

Synthesis and structure-activity relationships of 1-phenylpyrazoles as xanthine oxidase inhibitors.

A series of 1-phenylpyrazoles was evaluated for inhibitory activity against xanthine oxidase in vitro. Of the compounds prepared, 1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid (Y-700) had the most potent enzyme inhibition and displayed longer-lasting hypouricemic action than did allopurinol in a rat model of hyperuricemia induced by the uricase inhibitor potassium oxonate.

Prevention of amyloid-like deposition by a selective prolyl endopeptidase inhibitor, Y-29794, in senescence-accelerated mouse.

Our study was performed to assess the hypothesis that prolyl endopeptidase (PEP) would be functionally involved in the senescence-accelerated amyloid formation and that long-term inhibition of prolyl endopeptidase would suppress the progression of A beta-like deposition in the hippocampus of the senescence-accelerated mouse (SAM). Granular structures of A beta-LI were observed in the hippocampus and around cerebral microvessels of the SAM after immunohistochemical staining with specific anti-A beta antibody. Repeated treatment of the SAM with Y-29794 (1, 10, 20 mg/kg, p.o.), a specific inhibitor of prolyl endopeptidase, significantly reduced the number and density of A beta-positive granular structures in the hippocampus of the SAM, after digital image analysis with NIH Image software. Furthermore, the characteristic biphasic distribution of the digitized density of the granules was significantly modulated after the treatment with Y-29794. These results suggest that chronic treatment of the SAM with Y-29794, a nonpeptide inhibitor of prolyl endopeptidase, prevents the progression of A beta-like deposition in the hippocampus of the SAM.

Y-26763 protects the canine heart from a stunning injury through opening of the KATP channels.

The present study describes the protective effects of the ATP-sensitive K+ (KATP) channel opener Y-26763 ((-)-(3S,4R-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl -2H-1-benzopyran-3-ol), on a model of reversible ischemia/reperfusion injury ('stunned' myocardium). Stunning was caused by 10-min occlusion of the left circumflex coronary artery followed by 3-h reperfusion in pentobarbital anesthetized beagle dogs. This procedure reduced by over 80% myocardial segment function measured by sonomicrometry in control preparations. Y-26763, administered 10 min before the left circumflex coronary artery occlusion, at a dose (3 micrograms/kg, i.v.) lacking significant systemic hemodynamic effects, produced a rapid and marked (80%) recovery of the shortening of the ischemic segment. By contrast, nifedipine (1 microgram/kg plus 0.2 microgram/kg per min, i.v.) did not ameliorate postischemic function. Glibenclamide, administered before Y-26763 at a dose (0.3 mg/kg, i.v.) that did not affect adversely hemodynamics and stunning injury negated the beneficial action of Y-26763. However, glibenclamide failed to do so when administered 2 min before starting reperfusion. The ischemia/reperfusion areas, which were measured by digital image analysis with NIH image software, were similar among experimental groups. Overall, these results indicate that Y-26763 protects the canine myocardium from reversible ischemia/reperfusion injury, probably through activation of myocardial KATP channels which appear to be involved in affording protection during the ischemic insult and not at the reperfusion.

Principal involvement of cyclooxygenase-1-derived prostaglandins in the c-fos expression of the rat hind brain following visceral stimulation with acetic acid.

We investigated the relationship between c-fos expression in the hind brain and peritoneal prostaglandin (PG) synthesis after visceronociceptive stimulation with acetic acid in rats. Time-course studies on the mRNA expression for c-fos in the hind brain and cyclooxygenase (COX) isoforms in the peritoneal cells, as well as on the peritoneal 6-keto-PGF1alpha accumulation, after stimulation indicated that COX-1 but not COX-2 was responsible for the peritoneal synthesis of PGs which were suggested to evoke c-fos expression in the hind brain. Pharmacological experiments using mofezolac, a preferential inhibitor against COX-1, and NS-398, a selective inhibitor against COX-2, confirmed the involvement of COX-1 derived PGs in the induction of c-fos expression in the hind brain following the noxious stimulation.

Colocalization of prolyl endopeptidase and amyloid beta-peptide in brains of senescence-accelerated mouse.

Prolyl endopeptidase-like immunoreactivity (PEP-LI) was detected and compared with amyloid beta-peptide-like immunoreactivity (A beta-LI) in the brains of senescence-accelerated mouse (SAM). Granular structures of PEP-LI in the hippocampus appeared progressively, and age- and strain-dependently to form deposits which distributed morphologically similar and closely to those of A beta-LI. These results suggest that PEP has functional relevance to amyloidgenesis in brains of SAM.

Y-27152, a long-acting K+ channel opener with less tachycardia: antihypertensive effects in hypertensive rats and dogs in conscious state.

(+)-(3S,4R)-4-(N-Acetyl-N-benzyloxyamino)-6-cyano-3,4-dihydro-2,2- dimethyl- 2H-1-benzopyran-3-ol (Y-27152) is a new K+ channel opener with a long duration of action and less tachycardia. In this study, Y-27152 was compared with a K+ channel opener lemakalim and a Ca++ channel blocker nifedipine for antihypertensive activity in conscious spontaneously hypertensive rats (SHR) and two-kidney, one-clip renal hypertensive dogs (RHD). In conscious SHR, Y-27152 (0.1-1 mg/kg, p.o.) produced long-lasting dose-related decreases in systolic blood pressure. At 1 mg/kg, the maximum response occurred 5 to 7 hr after dosing, and 24 hr later, the pressure was still significantly reduced. Heart rate was not changed by these doses of Y-27152, whereas equihypotensive doses of lemakalim or nifedipine were strongly tachycardic. The cardiovascular effects of Y-27152 were antagonized by glibenclamide (20 mg/kg, i.v.). In conscious unrestrained RHD, Y-27152 at doses of 0.01, 0.03 and 0.1 mg/kg lowered blood pressure with a slow onset and long duration of action and had only a minimal effect on heart rate, whereas both lemakalim and nifedipine reduced blood pressure and markedly increased heart rate. No tolerance to the antihypertensive effect of Y-27152 (0.1 mg/kg) occurred during an 8-week repeated daily dosing to RHD and plasma renin activity, and aldosterone levels were not elevated during this period. In rat aortic rings contracted with 20 mM KCl, Y-27152 did not modify the tension; however, its desbenzyl form (Y-26763) produced vasorelaxation, and this effect was antagonized competitively by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)