Design of two new chemotypes for inhibiting the Janus kinase 2 by scaffold morphing

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 6, 2010, Pages 1858-1860

  Furet, Pascal ^a   Gerspacher, Marc ^a   Pissot Soldermann, Carole ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Kinase inhibitor design; Scaffold morphing

Indexed keywords

ANTINEOPLASTIC AGENT; JANUS KINASE 2 INHIBITOR; JANUS KINASE INHIBITOR;

ARTICLE; DRUG DESIGN; DRUG RESEARCH; DRUG SCREENING; DRUG STRUCTURE; STRUCTURE ACTIVITY RELATION;

DRUG DESIGN; JANUS KINASE 2; MODELS, MOLECULAR; PROTEIN KINASE INHIBITORS;

EID: 77549086187     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.01.151     Document Type: Article

References (18)

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18. In our model, the designed C-H···O interaction had the attributes of a H-bond (see Ref. 13): a distance between the proton and the acceptor oxygen atom of 2.3 Å which is significantly less than the sum of the van der Waals radii (2.7 Å), an angle C-H···O of 140° approaching the ideal value of 180° (linearity) and an elevation angle of 30° approaching the ideal value of 0° indicating the tendency of the H···O contact to lie in the plane containing the oxygen lone pairs. A crystal structure of compound 4 in complex with the kinase domain of JAK2 was subsequently solved (Ref. 7). It fully confirmed the validity of the design concept. In this structure a C-H···O pseudo hydrogen bond is observed between the C-H group in position 3 of the quinoxaline ring and the backbone carbonyl oxygen atom of residue L932. The geometric parameters of this hydrogen bond are the following: distance proton-oxygen of 2.34 Å, angle C-H···O of 132° and elevation angle of 40.4°.