19735-44-5Relevant academic research and scientific papers
Identification, Structure-Activity Relationship, and Biological Characterization of 2,3,4,5-Tetrahydro-1 H-pyrido[4,3-b]indoles as a Novel Class of CFTR Potentiators
Brindani, Nicoletta,Gianotti, Ambra,Giovani, Simone,Giacomina, Francesca,Di Fruscia, Paolo,Sorana, Federico,Bertozzi, Sine Mandrup,Ottonello, Giuliana,Goldoni, Luca,Penna, Ilaria,Russo, Debora,Summa, Maria,Bertorelli, Rosalia,Ferrera, Loretta,Pesce, Emanuela,Sondo, Elvira,Galietta, Luis J. V.,Bandiera, Tiziano,Pedemonte, Nicoletta,Bertozzi, Fabio
supporting information, p. 11169 - 11194 (2020/10/09)
Cystic fibrosis (CF) is a life-threatening autosomal recessive disease, caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel. CFTR modulators have been reported to address the basic defects associated with CF-causing mutations, partially restoring the CFTR function in terms of protein processing and/or channel gating. Small-molecule compounds, called potentiators, are known to ameliorate the gating defect. In this study, we describe the identification of the 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole core as a novel chemotype of potentiators. In-depth structure-activity relationship studies led to the discovery of enantiomerically pure 39 endowed with a good efficacy in rescuing the gating defect of F508del-and G551D-CFTR and a promising in vitro druglike profile. The in vivo characterization of γ-carboline 39 showed considerable exposure levels and good oral bioavailability, with detectable distribution to the lungs after oral administration to rats. Overall, these findings may represent an encouraging starting point to further expand this chemical class, adding a new chemotype to the existing classes of CFTR potentiators.
(1 R,2 R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3- b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A potent and highly selective cathepsin k inhibitor for the treatment of osteoarthritis
Dossetter, Alexander G.,Beeley, Howard,Bowyer, Jonathan,Cook, Calum R.,Crawford, James J.,Finlayson, Jonathan E.,Heron, Nicola M.,Heyes, Christine,Highton, Adrian J.,Hudson, Julian A.,Jestel, Anja,Kenny, Peter W.,Krapp, Stephan,Martin, Scott,MacFaul, Philip A.,McGuire, Thomas M.,Gutierrez, Pablo Morentin,Morley, Andrew D.,Morris, Jeffrey J.,Page, Ken M.,Ribeiro, Lyn Rosenbrier,Sawney, Helen,Steinbacher, Stefan,Smith, Caroline,Vickers, Madeleine
supporting information; experimental part, p. 6363 - 6374 (2012/09/25)
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
Novel Compound - 827
-
Page/Page column 14, (2009/01/23)
The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X. Of particular interest are diseases associated with Cathepsin K.
