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

Srinivas Reddy Chirapu; Boobalan Pachaiyappan; Hikmet F. Nural; Xin Cheng; Hongbin Yuan; David C. Lankin; Samer O. Abdul-Hay; Gregory R.J. Thatcher; Yong Shen; Alan P. Kozikowski; Pavel A. Petukhov

doi:10.1016/j.bmcl.2008.10.096

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

Srinivas Reddy Chirapu, Boobalan Pachaiyappan, Hikmet F. Nural, Xin Cheng, Hongbin Yuan, David C. Lankin, Samer O. Abdul-Hay, Gregory R.J. Thatcher, Yong Shen, Alan P. Kozikowski, Pavel A. Petukhov

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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 Aβ40 production in N2a cells stably transfected with Swedish human APP.

Original language	English (US)
Pages (from-to)	264-274
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2008.10.096
State	Published - Jan 1 2009
Externally published	Yes

Keywords

Alzheimer
Aspartic protease
BACE1
Computer-aided molecular design

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2008.10.096

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Chirapu, S. R., Pachaiyappan, B., Nural, H. F., Cheng, X., Yuan, H., Lankin, D. C., Abdul-Hay, S. O., Thatcher, G. R. J., Shen, Y., Kozikowski, A. P., & Petukhov, P. A. (2009). Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors. Bioorganic and Medicinal Chemistry Letters, 19(1), 264-274. https://doi.org/10.1016/j.bmcl.2008.10.096

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title = "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 Aβ40 production in N2a cells stably transfected with Swedish human APP.",

keywords = "Alzheimer, Aspartic protease, BACE1, Computer-aided molecular design",

author = "Chirapu, {Srinivas Reddy} and Boobalan Pachaiyappan and Nural, {Hikmet F.} and Xin Cheng and Hongbin Yuan and Lankin, {David C.} and Abdul-Hay, {Samer O.} and Thatcher, {Gregory R.J.} and Yong Shen and Kozikowski, {Alan P.} and Petukhov, {Pavel A.}",

note = "Funding Information: This research is supported by NIH R21 AG027454 (P.A.P.) and NIH AG025888 (Y.S.), Arizona Alzheimer Consortium (Y.S.), and Hans Vahlteich endowment program grant of College of Pharmacy (P.A.P.) at University of Illinois at Chicago. G.T and S.O.A are grateful for the kind gift of N2a cells from Dr. Gopal Thinakaran (University of Chicago, Chicago, IL). We thank Subash Velaparthi, Gilles Pieffet, and Reaz Uddin for useful comments and suggestions. The authors thank OpenEye Scientific Software for providing academic license for the modeling software.",

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doi = "10.1016/j.bmcl.2008.10.096",

language = "English (US)",

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AU - Chirapu, Srinivas Reddy

AU - Pachaiyappan, Boobalan

AU - Nural, Hikmet F.

AU - Cheng, Xin

AU - Yuan, Hongbin

AU - Lankin, David C.

AU - Abdul-Hay, Samer O.

AU - Thatcher, Gregory R.J.

AU - Shen, Yong

AU - Kozikowski, Alan P.

AU - Petukhov, Pavel A.

N1 - Funding Information: This research is supported by NIH R21 AG027454 (P.A.P.) and NIH AG025888 (Y.S.), Arizona Alzheimer Consortium (Y.S.), and Hans Vahlteich endowment program grant of College of Pharmacy (P.A.P.) at University of Illinois at Chicago. G.T and S.O.A are grateful for the kind gift of N2a cells from Dr. Gopal Thinakaran (University of Chicago, Chicago, IL). We thank Subash Velaparthi, Gilles Pieffet, and Reaz Uddin for useful comments and suggestions. The authors thank OpenEye Scientific Software for providing academic license for the modeling software.

PY - 2009/1/1

Y1 - 2009/1/1

N2 - 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 Aβ40 production in N2a cells stably transfected with Swedish human APP.

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KW - Alzheimer

KW - Aspartic protease

KW - BACE1

KW - Computer-aided molecular design

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

Abstract

Keywords

ASJC Scopus subject areas

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