Structure-based design of substituted piperidines as a new class of highly efficacious oral direct renin inhibitors

ACS Medicinal Chemistry Letters

Volumn 5, Issue 7, 2014, Pages 787-792

  Ehara, Takeru ^a   Irie, Osamu ^a   Kosaka, Takatoshi ^a   Kanazawa, Takanori ^a   Breitenstein, Werner ^b   Grosche, Philipp ^b   Ostermann, Nils ^b   Suzuki, Masaki ^a   Kawakami, Shimpei ^a   Konishi, Kazuhide ^a   Hitomi, Yuko ^a   Toyao, Atsushi ^a   Gunji, Hiroki ^a   Cumin, Frederic ^b   Schiering, Nikolaus ^b   Wagner, Trixie ^b   Rigel, Dean F ^b   Webb, Randy L ^b   Maibaum, Jurgen ^b   Yokokawa, Fumiaki ^a  

^a Novartis Institutes for BioMedical Research   (Japan)

^b NOVARTIS PHARMA AG   (Switzerland)

Author keywords

3,5 piperidines; aspartic protease; Renin inhibitor; structure based design

Indexed keywords

PIPERIDINE DERIVATIVE; RENIN INHIBITOR;

ARTICLE; BLOOD PRESSURE; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; HIGH THROUGHPUT SCREENING; HUMAN; IN VITRO STUDY; NONHUMAN; PRIORITY JOURNAL; RAT; TRANSGENIC RAT;

EID: 84904330469     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml500137b     Document Type: Article

References (22)

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22. 4-Hydroxy-3,4-substituted piperidine DRIs were reported recently: Chen, A.; Cauchon, E.; Chefson, A.; Dolman, S.; Ducharme, Y.; Dube, D.; Falgueyret, J. P.; Fournier, P. A.; Gagne, S.; Gallant, M.; Grimm, E.; Han, Y.; Houle, R.; Huang, J. Q.; Hughes, G.; Juteau, H.; Lacombe, P.; Lauzon, S.; Levesque, J. F.; Liu, S.; MacDonald, D.; Mackay, B.; McKay, D.; Percival, M. D.; St-Jacques, R.; Toulmond, S. Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of tertiary alcohol-bearing piperidines Bioorg. Med. Chem. Lett. 2011, 21, 3976-3981 Notably, the modeling structure and SAR observed for these 3,4-piperidine inhibitors suggested the 4-OH group to be directed toward the solvent space without any direct binding interactions to the enzyme, which is in contrast to the experimental observations made for the 4-hydroxy-3,5-piperidine series reported here