Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility

被引：34

作者：

Jia, Lanqi ^{[1
]}

Simpson, Robert D. ^{[1
]}

Yuan, Jing ^{[1
]}

Xu, Zhenrong ^{[1
]}

Zhao, Wei ^{[1
]}

Cacatian, Salvacion ^{[1
]}

Tice, Colin M. ^{[1
]}

Guo, Joan ^{[1
]}

Ishchenko, Alexey ^{[1
]}

Singh, Suresh B. ^{[1
]}

Wu, Zhongren ^{[1
]}

McKeever, Brian M. ^{[1
]}

Bukhtiyarov, Yuri ^{[1
]}

Johnson, Judith A. ^{[1
]}

Doe, Christopher P. ^{[2
]}

Harrison, Richard K. ^{[1
]}

McGeehan, Gerard M. ^{[1
]}

Dillard, Lawrence W. ^{[1
]}

Baldwin, John J. ^{[1
]}

Claremon, David A. ^{[1
]}

机构：

[1] Vitae Pharmaceut, Ft Washington, PA 19034 USA

[2] GlaxoSmithKline, King Of Prussia, PA 19406 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2011年 / 2卷 / 10期

关键词：

Renin; aspartyl protease; hypertension; structure-based drug design; OPTIMIZATION; DESIGN;

D O I：

10.1021/ml200137x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the c-yclohexylmethyl group occupying the SI pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

引用

页码：747 / 751

页数：5

共 24 条

[1] Update on tissue renin-angiotensin systems [J].

Bader, Michael ;

Ganten, Detlev .

JOURNAL OF MOLECULAR MEDICINE-JMM, 2008, 86 (06) :615-621

[2] Design and Preparation of Potent, Nonpeptidic, Bioavailable Renin Inhibitors [J].

Bezencon, Olivier ;

Bur, Daniel ;

Weller, Thomas ;

Richard-Bildstein, Sylvia ;

Remen, Lubos ;

Sifferlen, Thierry ;

Corminboeuf, Olivier ;

Grisostomi, Corinna ;

Boss, Christoph ;

Prade, Lars ;

Delahaye, Stephane ;

Treiber, Alexander ;

Strickner, Panja ;

Binkert, Christoph ;

Hess, Patrick ;

Steiner, Beat ;

Fischli, Walter .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (12) :3689-3702

[3] Addressing time-dependent CYP 3A4 inhibition observed in a novel series of substituted amino propanamide renin inhibitors, a case study [J].

Chen, Austin ;

Dube, Daniel ;

Dube, Laurence ;

Gagne, Sebastien ;

Gallant, Michel ;

Gaudreault, Mireille ;

Grimm, Erich ;

Houle, Robert ;

Lacombe, Patrick ;

Laliberte, Sebastien ;

Liu, Suzanna ;

MacDonald, Dwight ;

Mackay, Bruce ;

Martin, David ;

McKay, Dan ;

Powell, David ;

Levesque, Jean-Francois .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (17) :5074-5079

[4] SPECIES SPECIFICITY OF RENIN KINETICS IN TRANSGENIC RATS HARBORING THE HUMAN RENIN AND ANGIOTENSINOGEN GENES [J].

GANTEN, D ;

WAGNER, J ;

ZEH, K ;

BADER, M ;

MICHEL, JB ;

PAUL, M ;

ZIMMERMANN, F ;

RUF, P ;

HILGENFELDT, U ;

GANTEN, U ;

KALING, M ;

BACHMANN, S ;

FUKAMIZU, A ;

MULLINS, JJ ;

MURAKAMI, K .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (16) :7806-7810

[5] RENIN INHIBITORS [J].

GREENLEE, WJ .

MEDICINAL RESEARCH REVIEWS, 1990, 10 (02) :173-236

[6]

GREGG RE, 2011, AM DIAB ASS 71 SCI S

[7] Direct renin inhibition and the kidney [J].

Hollenberg, Norman K. .

NATURE REVIEWS NEPHROLOGY, 2010, 6 (01) :49-55

[8] Structural modification of the P2′ position of 2,7-dialkyl-substituted 5(S)-Amino-4(S)-hydroxy-8-phenyl-octanecarboxamides:: The discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets [J].

Maibaum, Juergen ;

Stutz, Stefan ;

Goeschke, Richard ;

Rigollier, Pascal ;

Yamaguchi, Yasuchika ;

Cumin, Frederic ;

Rahuel, Joseph ;

Baum, Hans-Peter ;

Cohen, Nissim-Claude ;

Schnell, Christian R. ;

Fuhrer, Walter ;

Gruetter, Markus G. ;

Schilling, Walter ;

Wood, Jeanette M. .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (20) :4832-4844

[9] Application of Direct Renin Inhibition to Chronic Kidney Disease [J].

Mende, Christian W. .

CARDIOVASCULAR DRUGS AND THERAPY, 2010, 24 (02) :139-149

[10]

Remuzzi Giuseppe, 2005, Kidney Int Suppl, pS57

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