ACS Medicinal Chemistry Letters
Letter
functions as a transition-state surrogate. The 4-hydroxyl group
is H-bonded to Ser76 of the flap being in a closed
conformation.23 The N-cyclopropyl group and the isopropyl-
substituted pyridyl moiety are positioned in the large
contiguous hydrophobic S1/S3 pocket, leaving the S3sp
unoccupied. The pyridyl nitrogen is in close H-bond distance
to the side chain hydroxyl of Thr77 located at the tip of the flap
domain. The data support the notion that this interaction is
indeed crucial for strong binding affinity, in particular for
inhibitors lacking interactions with the S3sp site. The carbonyl
oxygen of the prime-site amide linker forms an H-bond to the
backbone nitrogen of the flap Ser76, while the amide NH
functions as an H-bond donor to the carbonyl oxygen of Gly34.
The sec-butyl makes hydrophobic interactions to S1′, and the
terminal ethoxyethane group occupies the S2′ pocket.
In summary, novel highly potent cis-configured (3R,5S)-
piperidine-based DRIs were derived from a weakly active HTS
hit (compound 1). Structure-based modification of the prime-
site linker and optimization of the P3−P1 and P1′-P2′ portions
guided by X-ray crystallography significantly improved the in
vitro potency. The discovery of the N-alkyl substituted 6-pyridyl
as a novel high affinity P3 scaffold even in the absence of a P3sp
side chain constituted a breakthrough of our extensive
optimization efforts. The additional introduction of a hydroxyl
group on the piperidine core furnished several inhibitors with
improved PK profiles in rats. Inhibitor 31 demonstrated high in
vitro potency and off-target selectivity, an attractive phys-
icochemical and in vitro ADME profile, as well as excellent oral
bioavailability and long elimination half-life in rat. Inhibitor 31
showed high efficacy in the dTGR model with a dose-
dependent sustained blood pressure reduction observed for
more than 24 h after single oral dose administration.
their support in NMR studies. We thank Leslie Bell, Susanne
Glowienke, Martin Traebert, Steven Whitebread, and their
team members for their help in getting the profiling data of 31.
We thank Jason Elliott and Christopher M. Adams for their
critical reading of the manuscript.
ABBREVIATIONS
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RAAS, renin−angiotensin−aldosterone system; ACE, angio-
tensin converting enzyme; ADME, absorption, distribution,
metabolism, and excretion; DRI, direct renin inhibitor; HTS,
high-throughput screening; rh-renin, recombinant human
renin; Ac2O, acetic anhydride; Boc, tert-butoxycarbonyl;
(Boc)2O, di-tert-butyl dicarbonate; BopCl, bis(2-oxo-3-
oxazolidinyl)phosphinic chloride; DMF, dimethylformamide;
dTGR, double transgenic rat; EDCI·HCl, 1-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide hydrochloride; Et3N,
triethylamine; EtOAc, ethyl acetate; EtOH, ethyl alcohol;
̀
hERG, the human ether-a-go-go-related gene; HOAT, 1-
hydroxy-7-azabenzotriazol; mp, melting point; PK, pharmaco-
kinetics; RLM, rat liver microsomes; TcBocCl, 2,2,2-trichloro-
1,1-dimethylethyl chloroformate
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ASSOCIATED CONTENT
* Supporting Information
Full experimental details for compounds synthesized, exper-
imental procedures for biological assays, in vivo pharmacoki-
netics, in vivo pharmacology, and X-ray crystallographic
information for the rh-renin−inhibitor complexes. This material
■
S
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AUTHOR INFORMATION
Corresponding Author
*Tel: +65-6722-2931. Fax +65-6722-2982. E-mail: fumiaki.
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Present Addresses
§Novartis Institutes for BioMedical Research, 100 Technology
Square, Cambridge, Massachusetts 02139, United States
⊥Novartis Institute for Tropical Diseases, 10 Biopolis Road,
#05-01 Chromos, Singapore 138670.
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Geisse, S.; Bernd Gerhartz, B.; Richert, R.; Francotte, E.; Wagner, T.;
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank Hans-Peter Baum and Markus Sanner for IC50
determinations of renin inhibition and Marie-Helene Bellance,
Corinne Durand, and Paul Schultheiss for their technical
assistance. We thank Florence Zink and Allan D’Arcy for
protein crystallization. We also thank Masashi Furuichi and
Oliver Grosche for measuring the melting point and aqueous
solubility of 31 succinate. We acknowledge Virginia Casadas for
her dTGR study with 31, and Charles Babu and Bin Wang for
Kromer, M.; Kosaka, T.; Randy, L.; Webb, R. L.; Rigel, D. F.;
̈
Maibaum, J.; Baeschlin, D. K. A Novel Class of Oral Direct Renin
Inhibitors: Highly Potent 3,5-Disubstituted Piperidines Bearing a
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791
dx.doi.org/10.1021/ml500137b | ACS Med. Chem. Lett. 2014, 5, 787−792