Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors

Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-05, Vol.23 (10), p.3075-3080
Hauptverfasser:	Xu, Ying-zi, Yuan, Shendong, Bowers, Simeon, Hom, Roy K., Chan, Wayman, Sham, Hing L., Zhu, Yong L., Beroza, Paul, Pan, Hu, Brecht, Eric, Yao, Nanhua, Lougheed, Julie, Yan, Jiangli, Tam, Danny, Ren, Zhao, Ruslim, Lany, Bova, Michael P., Artis, Dean R.
Format:	Artikel
Sprache:	eng
Schlagworte:	Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - metabolism Aspartic Acid Endopeptidases - antagonists & inhibitors Aspartic Acid Endopeptidases - metabolism BACE1 inhibitor Dose-Response Relationship, Drug Drug Design Humans Isoquinolines - chemistry Isoquinolines - pharmacology Models, Molecular Molecular Structure Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology SAR Selectivity Structural based drug design Structure-Activity Relationship Thiophenes - chemistry Thiophenes - pharmacology
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Beschreibung
Zusammenfassung:	Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.03.009