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Discovery and characterization of AZD9272 and AZD6538 - Two novel mGluR5 negative allosteric modulators selected for clinical development
Raboisson, Patrick,Breitholtz-Emanuelsson, Anna,Dahlloef, Henrik,Kers, Annika,Minidis, Alexander B. E.,Nordmark, Anna,Stroem, Peter,Terelius, Ylva,Wensbo, David,Edwards, Louise,Isaac, Methvin,Jarvie, Keith,Slassi, Abdelmalik,Wilson, Julie M.,Xin, Tao,Heaton, William L.,Sheehan, Susan M.,McLeod, Donald A.
, p. 6974 - 6979,6 (2020/09/02)
AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.
Fluorine-flanked congested sites: Minimal, though perceptible buttressing effects on the proton mobility of arenes
Heiss, Christophe,Leroux, Frederic,Schlosser, Manfred
, p. 5242 - 5247 (2007/10/03)
(2,6-Difluorophenyl)trimethylsilane, -triethylsilane and -triisopropylsilane undergo sec-butyllithium-mediated metalation at the 3- and 4-position (ortho and meta relative to the halogen) in ratios of 99.6:0.4, 98:2 and 95:5, respectively. The steric pressure transmitted by the fluorine atoms can be increased if the trialkylsilyl group is locked up on the other side by a relatively voluminous substituent. Whereas (2,6-difluorophenyl)triethylsilane is attacked by lithium 2,2,6,6-tetramethylpiperidide under deprotonation of the 4- and 5-position in a ratio of 99.4:0.6, the proportion of "ortho"/ "meta" metalation changes to 84:16 when (2-bromo-6-fluorophenyl) triethylsilane acts as the substrate. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.