Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

被引：34

作者：

Mandal, Mihirbaran ^{[1
]}

Wu, Yusheng ^{[1
]}

Misiaszek, Jeffrey ^{[1
]}

Li, Guoqing ^{[1
]}

Buevich, Alexei ^{[1
]}

Caldwell, John P. ^{[1
]}

Liu, Xiaoxiang ^{[1
]}

Mazzola, Robert D. ^{[1
]}

Orth, Peter ^{[1
]}

Strickland, Corey ^{[1
]}

Voigt, Johannes ^{[1
]}

Wang, Hongwu ^{[1
]}

Zhu, Zhaoning ^{[1
]}

Chen, Xia ^{[2
]}

Grzelak, Michael ^{[2
]}

Hyde, Lynn A. ^{[2
]}

Kuvelkar, Reshma ^{[2
]}

Leach, Prescott T. ^{[2
]}

Terracina, Giuseppe ^{[2
]}

Zhang, Lili ^{[2
]}

Zhang, Qi ^{[2
]}

Michener, Maria S. ^{[3
]}

Smith, Brad ^{[3
]}

Cox, Kathleen ^{[5
]}

Grotz, Diane ^{[5
]}

Favreau, Leonard ^{[5
]}

Mitra, Kaushik ^{[5
]}

Kazakevich, Irina ^{[4
]}

McKittrick, Brian A.

Greenlee, William ^{[1
]}

Kennedy, Matthew E. ^{[2
]}

Parker, Eric M. ^{[2
]}

Cumming, Jared N. ^{[1
]}

Stamford, Andrew W. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Global Chem, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[2] Merck Res Labs, Dept Neurosci, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[3] Merck Res Labs, Dept Safety Assessment & Lab Anim Res, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[4] Merck Res Labs, Dept Discovery Pharmaceut Sci, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[5] Merck Res Labs, Dept Pharmacokinet Pharmacodynam & Drug Metab, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 07期

关键词：

X-RAY CRYSTALLOGRAPHY; TREATING ALZHEIMERS-DISEASE; IN-VIVO; SECRETASE INHIBITORS; ROBUST REDUCTION; DRUG DISCOVERY; CELL BIOLOGY; POTENT; HYPOTHESIS; EFFICACY;

D O I：

10.1021/acs.jmedchem.5b01995

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in 51 was pursued. Optimization of the pyrimidine substituent that binds in the S2' S2 '' pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex A beta(40) in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central A beta in nonrodent preclinical species.

引用

页码：3231 / 3248

页数：18

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