SDZ-MKS-492

The polymorphic behavior of the purine derivative MKS 492 was studied with investigations of suspensions of selected samples in different solvents and of samples obtained by crystallizationsThe samples were analyzed by DSC, TG and x-ray diffraction.Six different crystalline modifications called A, B, B', C, D and E and an amorphous form were identified.Four pure crystalline modifications, A, B, C and D have been manufactured and characterized by DSC, x-ray, IR, solubilities, densities, hygroscopicity and dissolution measurements.The four forms A, C, D and E are monotrop to the form B.The form B is enantiotrope to the form B', which revealed the highest m.p. of all known polymorphs.This form B' is only stable at high temperatureTemperature resolved x-ray diffraction was very helpful for proper interpretation of the thermal events.The melting peaks of the forms A and C and the endothermic peak corresponding to the enantiotropic transition B into B' occur in a narrow range of temperatureThe form B which is the most stable one at room temperature has been chosen for further development.Quant. methods to determine the content of the forms A, C and D in samples of form B or to determine the content of form A, B and D in form C have been developed by using x-ray diffraction.Limits of detection are 1 or 2%.For the quant. determination of the amorphous fraction, x-ray diffraction and microcalorimetry are compared.For high amounts of the amorphous fraction, the x-ray diffraction method is preferred because it is faster.Microcalorimetry is very attractive for levels below 10% amorphous content.The lowest limit of detection is obtained by microcalorimetry, about 1%.

Reactive oxygen-derived free radical species have been implicated in the pathogenesis and pathophysiology of inflammatory lung diseases. In a guinea pig model of aerosolized endotoxin-induced bronchial hyperresponsiveness to substance P, a possible involvement of oxidative lung injury was assessed by measuring the changes in membrane-bound neutral endopeptidase activity in the airway tissues and the level of lipid peroxides in the plasma. Vehicle-treated animals developed a neutrophilic airway inflammation, bronchial hyperresponsiveness to substance P associated with neutral endopeptidase hypoactivity, and elevation of lipid peroxides at 18 to 24 h after an exposure to endotoxin (75 microgram/ml, 40 min). A nonselective phosphodiesterase inhibitor, aminophylline, and selective phosphodiesterase isoenzyme inhibitors, SDZ-ISQ-844 (type III/IV) and SDZ-MKS-492 (type III), attenuated the neutrophilic airway inflammation induced by endotoxin. Aminophylline, SDZ-MKS-492, and a superoxide anion-generating NADPH-oxidase inhibitor apocynin inhibited bronchial hyperresponsiveness to substance P with attenuation of neutral endopeptidase inactivation induced by endotoxin. SDZ-ISQ-844, SDZ-MKS-492, and apocynin attenuated the elevation of lipid peroxides. The generation of hypochlorite (OCl-) from whole blood leukocytes was attenuated by aminophylline, SDZ-ISQ-844, SDZ-MKS-492, and apocynin at 1 to 2 h after exposure. These results suggest that reactive oxygen-derived free radical species-mediated oxidative lung injury may play an important role in endotoxin-induced bronchial hyperresponsiveness to substance P, and that phosphodiesterase isoenzyme inhibitors may be potentially useful as anti-inflammatory drugs.