Eric Brecht

Publications (4)10.6 Total impact

• Article: Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors.

  Ying-Zi Xu, Shendong Yuan, Simeon Bowers, Roy K Hom, Wayman Chan, Hing L Sham, Yong L Zhu, Paul Beroza, Hu Pan, Eric Brecht, Nanhua Yao, Julie Lougheed, Jiangli Yan, Danny Tam, Zhao Ren, Lany Ruslim, Michael P Bova, Dean R Artis
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  ABSTRACT: 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.
  Bioorganic & medicinal chemistry letters 03/2013; · 2.65 Impact Factor
• Article: Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.

  Simeon Bowers, Ying-Zi Xu, Shendong Yuan, Gary D Probst, Roy K Hom, Wayman Chan, Andrei W Konradi, Hing L Sham, Yong L Zhu, Paul Beroza, Hu Pan, Eric Brecht, Nanhua Yao, Julie Lougheed, Danny Tam, Zhao Ren, Lany Ruslim, Michael P Bova, Dean R Artis
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  ABSTRACT: The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.
  Bioorganic & medicinal chemistry letters 02/2013; · 2.65 Impact Factor
• Article: Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: structure-activity relationship of the aryl region.

  Gary D Probst, Simeon Bowers, Jennifer M Sealy, Brian Stupi, Darren Dressen, Barbara M Jagodzinska, Jose Aquino, Andrea Gailunas, Anh P Truong, Luke Tso, [......], May Lin, Dean R Artis, Lany Ruslim, Michael P Bova, Sukanto Sinha, Ted A Yednock, Shawn Gauby, Wes Zmolek, Kevin P Quinn, John-Michael Sauer
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  ABSTRACT: The structure-activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1.
  Bioorganic & medicinal chemistry letters 10/2010; 20(20):6034-9. · 2.65 Impact Factor
• Article: Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents.

  Anh P Truong, Gary D Probst, Jose Aquino, Larry Fang, Louis Brogley, Jennifer M Sealy, Roy K Hom, John A Tucker, Varghese John, Jay S Tung, [......], Eric Brecht, Hu Pan, Dean R Artis, Lany Ruslim, Michael P Bova, Sukanto Sinha, Ted A Yednock, Wes Zmolek, Kevin P Quinn, John-Michael Sauer
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  ABSTRACT: Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.
  Bioorganic & medicinal chemistry letters 08/2010; 20(16):4789-94. · 2.65 Impact Factor