Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors.

A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency.

Synthesis and multiparametric evaluation of thiadiazoles and oxadiazoles as diacylglycerol acyltransferase type 1 inhibitors.

Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.

Thiadiazoles as new inhibitors of diacylglycerol acyltransferase type 1.

A novel class of DGAT1 inhibitors containing a thiadiazole core has been discovered. Chemical optimization lead to inhibitors of human DGAT1 with an appropriate ADME profile and that show in vivo activity in target tissues.

Propofol differently alters vascular reactivity in normotensive and hypertensive rats.

1. The effect of propofol on arterial tone in hypertension is poorly understood. We examined the effect of increasing concentrations of propofol (5.6 x 10-8 to 2.8 x 10-3 mol/L) on isometric tension developed by noradrenaline (10-7 mol/L)-contracted aortic rings from 12-week-old Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. In both WKY rats and SHR, propofol induced a dose-dependent inhibition of contraction induced by noradrenaline, but the amplitude of relaxation was larger in the SHR than in WKY rats. 3. The effects of propofol was endothelium independent in WKY rats, whereas in SHR relaxation induced by propofol was greater in endothelium-intact than in endothelium-denuded rings. 4. In conclusion, we found significant differences in the effect of propofol in hypertensive rats, which may be related to differences in structural and functional properties of the arterial wall observed in hypertension.

Erectile dysfunction in spontaneously hypertensive rats: pathophysiological mechanisms.

Hypertensive men have a higher prevalence of erectile dysfunction (ED) than the general population. Experimental evidence of ED in hypertensive animals is scarce. This study evaluates the erectile function of spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) in vivo by the increase in intracavernosal pressure after electrical stimulation of the cavernous nerve (CN) and by isometric tension studies on corporal strips. Frequency-dependent erectile responses to CN stimulations were reduced in SHR. Phenylephrine induced lower corporal contractions in SHR although pD2 values were similar to WKY. Endothelium-dependent relaxations to ACh were impaired significantly in SHR, and indomethacin improved these relaxations in both WKY and SHR, the latter thus reaching values similar to WKY. Corporal relaxations to sodium nitroprusside were enhanced in SHR. Thus a dysfunctional alpha-adrenergic contraction of the corporal smooth muscle, an increased cyclooxygenase-dependent constrictor tone, and/or a defect in endothelium-dependent reactivity are associated with the altered erectile mechanisms in SHR. Drugs targeting endothelial dysfunction may delay the occurrence of ED as a complication of hypertension.

Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain.

N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) is a novel low-affinity, noncompetitive N-methyl-d-aspartate receptor antagonist. The current study compared the antinociceptive effects of CHF3381 with those of gabapentin and memantine in in vitro and in vivo models of pain. In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon. CHF3381 suppressed the maintenance of carrageenan-induced thermal and mechanical hyperalgesia in the rat with a minimum significantly effective dose (MED) of 30 mg/kg p.o. Memantine produced a partial reversal of both thermal and mechanical hyperalgesia (MED = 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED = 10 mg/kg s.c.), but did not affect thermal hyperalgesia. In the mouse formalin test, CHF3381 and memantine preferentially inhibited the late phase (MED = 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED = 30 mg/kg s.c.). Unlike morphine, CHF3381 chronic administration was not accompanied by the development of tolerance in the formalin test. Furthermore, morphine tolerance did not cross-generalize to CHF3381. In rats with a sciatic nerve injury, CHF3381 relieved both cold and mechanical allodynia (MED = 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED = 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED = 50 mg/kg p.o.). Memantine (15 mg/kg i.p.) produced an antinociceptive effect, whereas gabapentin (100 mg/kg p.o.) had no significant effect. Thus, CHF3381 may be useful for the therapy of peripheral painful neuropathies.