Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents.

Truong, Anh P; Probst, Gary D; Aquino, Jose; Fang, Larry; Brogley, Louis; Sealy, Jennifer M; Hom, Roy K; Tucker, John A; John, Varghese; Tung, Jay S; Pleiss, Michael A; Konradi, Andrei W; Sham, Hing L; Dappen, Michael S; Tóth, Gergley; Yao, Nanhua; Brecht, Eric; Pan, Hu; Artis, Dean R; Ruslim, Lany; Bova, Michael P; Sinha, Sukanto; Yednock, Ted A; Zmolek, Wes; Quinn, Kevin P; Sauer, John-Michael

Truong, Anh P; Probst, Gary D; Aquino, Jose; Fang, Larry; Brogley, Louis; Sealy, Jennifer M; Hom, Roy K; Tucker, John A; John, Varghese; Tung, Jay S; Pleiss, Michael A; Konradi, Andrei W; Sham, Hing L; Dappen, Michael S; Tóth, Gergley; Yao, Nanhua; Brecht, Eric; Pan, Hu; Artis, Dean R; Ruslim, Lany; Bova, Michael P; Sinha, Sukanto; Yednock, Ted A; Zmolek, Wes; Quinn, Kevin P; Sauer, John-Michael.

Affiliation

Truong AP; Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States.

Bioorg Med Chem Lett ; 20(16): 4789-94, 2010 Aug 15.

Article in En | MEDLINE | ID: mdl-20634069

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.

Subject(s)

Acetamides/chemistry; Amyloid Precursor Protein Secretases/antagonists & inhibitors; Aspartic Acid Endopeptidases/antagonists & inhibitors; Butanols/chemistry; Cyclohexylamines/chemistry; Protease Inhibitors/chemistry; Acetamides/chemical synthesis; Acetamides/pharmacokinetics; Amyloid Precursor Protein Secretases/metabolism; Aspartic Acid Endopeptidases/metabolism; Binding Sites; Butanols/chemical synthesis; Butanols/pharmacokinetics; Cell Membrane Permeability/drug effects; Crystallography, X-Ray; Cyclohexylamines/chemical synthesis; Cyclohexylamines/pharmacokinetics; Humans; Protease Inhibitors/chemical synthesis; Protease Inhibitors/pharmacokinetics; Structure-Activity Relationship

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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protease Inhibitors / Aspartic Acid Endopeptidases / Cyclohexylamines / Butanols / Amyloid Precursor Protein Secretases / Acetamides Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2010 Type: Article Affiliation country: United States

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