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Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors.

ABSTRACT: A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand 5b reduced 65% of Abeta40 production in N2a cells stably transfected with Swedish human APP.

SUBMITTER: Chirapu SR

PROVIDER: S-EPMC2643073 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors.

Chirapu Srinivas Reddy SR Pachaiyappan Boobalan B Nural Hikmet F HF Cheng Xin X Yuan Hongbin H Lankin David C DC Abdul-Hay Samer O SO Thatcher Gregory R J GR Shen Yong Y Kozikowski Alan P AP Petukhov Pavel A PA

Bioorganic & medicinal chemistry letters 20081025 1

A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand 5b reduced 65% of Abeta40 production in N2a cells stably ...[more]

PMID: 19013792

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