Fused pyrimidine derivativesFused pyrimidine derivatives R 0515 A Novel Orally Active Inhibitor of HLE. -The synthesis of compound (IX), a potential orally active HLE inhibitor for the treatment of inflammatory bronchopulmonary diseases such as COPD and chronic bronchitis, is presented. Ex vivo experiments in mice and the in vivo acute HLE induced mouse lung haemorrhage model demonstrate the remarkable oral activity of this new substance. -(VARGA*, M.; KAPUI, Z.; BATORI, S.; NAGY, L. T.; VASVARI-DEBRECZY, L.; MIKUS, E.; URBAN-SZABO, K.; ARANYI, P.; Eur. J. Med. Chem. 38 (2003) 4, 421-425; Discovery Res., CHINOIN Co. Ltd., H-1045 Budapest, Hung.; Eng.) -H. Haber 37-130
Drotaverine is considered an inhibitor of cyclic-39,59-nucleotidephophodiesterase (PDE) enzymes; however, published receptor binding data also support the potential L-type voltage-operated calcium channel (L-VOCC) blocking effect of drotaverine. Hence, in this work, we focus on the potential L-VOCC blocking effect of drotaverine by using L-VOCC-associated functional in vitro models. Accordingly, drotaverine and reference agents were tested on KCl-induced guinea pig tracheal contraction. Drotaverine, like the L-VOCC blockers nifedipine or diltiazem, inhibited the KCl-induced inward Ca 21 -induced contraction in a concentration-dependent fashion. The PDE inhibitor theophylline had no effect on the KCl-evoked contractions, indicating its lack of inhibition on inward Ca 21 flow.
Asthma is a common chronic inflammatory disease. Although effective asthma therapies are available, part of asthmatic population do not respond to these treatment options. In this work we present the result of development of CPL302-253 molecule, a selective PI3Kδ inhibitor. This molecule is intended to be a preclinical candidate for dry powder inhalation in asthma treatment. Studies we performed showed that this molecule is safe and effective PI3Kδ inhibitor that can impact many immune functions. We developed a short, 15-day HDM induced asthma mouse model, in which we showed that CPL302-253 is able to block inflammatory processes leading to asthma development in vivo.
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