- Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity
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Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.
- Marugan, Juan J.,Zheng, Wei,Motabar, Omid,Southall, Noel,Goldin, Ehud,Westbroek, Wendy,Stubblefield, Barbara K.,Sidransky, Ellen,Aungst, Ronald A.,Lea, Wendy A.,Simeonov, Anton,Leister, William,Austin, Christopher P.
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experimental part
p. 1033 - 1058
(2011/04/25)
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- Synthesis of derivatives of thiophene using methyl 2-isothiocyanatobenzoate
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A variety of 2-substituted thiophenes is readily obtained from 2-(2-thienyl)-4H-3,1-benzothiazin-4-one (2), which is formed when thiophene reacts with methyl 2-isothiocyanatobenzoate (1) in the presence of anhydrous stannic chloride.
- Deck,Turner,Deck,Papadopoulos
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p. 343 - 347
(2007/10/03)
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- Discovery of potent cyclic GMP phosphodiesterase inhibitors. 2-Pyridyl- and 2-imidazolylquinazolines possessing cyclic GMP phosphodiesterase and thromboxane synthesis inhibitory activities
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Moderate cyclic GMP phosphodiesterase (cGMP-PDE, PDE V) inhibitor 2- phenyl-4-anilino-quinazoline (1) was identified utilizing MultiCASE assisted drug design (MCADD) technology. Modification of compound 1 was conducted at the 2-, 4-, and 6-positions of the quinazoline ring for enhancement of cGMP- PDE inhibitory activity. The 6-substituted 2-(imidazol-1-yl)-quinazolines are 1000 times more potent in in vitro PDE V enzyme assay than the well-known inhibitor zaprinast. The 6-substituted derivatives of 2-(3- pyridyl)quinazoline 84 and 2-(imidazol-1-yl)quinazoline 86 exhibited more than 1000-fold selectivity for PDE V over the other four PDE isozymes. In addition, cGMP-PDE inhibitors 64, 65, and 73 were found to have an additional property of thromboxane synthesis inhibitory activity.
- Lee,Konishi,Yu,Miskowski,Riviello,Macina,Frierson,Kondo,Sugitani,Sircar,Blazejewski
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p. 3547 - 3557
(2007/10/03)
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