Issue 1, 2010
From the journal:

MedChemComm

Synthesis and biological activity of new pyridone diaryl ether non-nucleoside inhibitors of HIV-1reverse transcriptase†

Joshua J. Kennedy-Smith,*a   Nidhi Arora,a   J. Roland Billedeau,a   Jennifer Fretland,e   Julie Q. Hang,d   Gabrielle M. Heilek,c   Seth F. Harris,b   Donald Hirschfeld,a   Hassan Javanbakht,c   Yu Li,d   Weiling Liang,a   Ralf Roetz,a   Mark Smith,a   Guoping Su,c   Judy M. Suh,a   Armando G. Villaseñor,b   Jeffrey Wu,a   Dennis Yasuda,a   Klaus Klumppd  and  Zachary K. Sweeney*a  

* Corresponding authors

a Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA
E-mail: joshua.kennedy_smith@roche.com, sweeney.zachary@gene.com

b Department of Discovery Technologies, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA

c Department of Viral Disease Biology, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA

d Department of Viral Disease Biochemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA

e Department of Non-Clinical Safety, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA

Abstract

New pyridone non-nucleoside reverse transcriptase inhibitors (NNRTIs) were prepared and several flexible routes to this class of inhibitor were identified. These NNRTIs were active inhibitors of the replication of wild-type and NNRTI-resistant HIV. Structure-based drug design was used to optimize the activity of the compounds against NNRTI-resistant mutants. The co-crystal structure of inhibitor 2b in the NNRTI binding pocket of HIV reverse transcriptase (HIVRT) is also described.

Graphical abstract: Synthesis and biological activity of new pyridone diaryl ether non-nucleoside inhibitors of HIV-1 reverse transcriptase

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Article information

DOI
https://doi.org/10.1039/C0MD00009D
Article type
Concise Article
Submitted
01 Feb 2010
Accepted
01 Mar 2010
First published
28 Apr 2010

Med. Chem. Commun., 2010,1, 79-83

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Synthesis and biological activity of new pyridone diaryl ether non-nucleoside inhibitors of HIV-1 reverse transcriptase

J. J. Kennedy-Smith, N. Arora, J. R. Billedeau, J. Fretland, J. Q. Hang, G. M. Heilek, S. F. Harris, D. Hirschfeld, H. Javanbakht, Y. Li, W. Liang, R. Roetz, M. Smith, G. Su, J. M. Suh, A. G. Villaseñor, J. Wu, D. Yasuda, K. Klumpp and Z. K. Sweeney, Med. Chem. Commun., 2010, 1, 79 DOI: 10.1039/C0MD00009D

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