Format

Send to

Choose Destination
Bioorg Med Chem Lett. 2014 Aug 15;24(16):4031-4. doi: 10.1016/j.bmcl.2014.06.002. Epub 2014 Jun 12.

Discovery of triazines as selective PDE4B versus PDE4D inhibitors.

Author information

1
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA. Electronic address: thagen@niu.edu.
2
Tetra Discovery Partners LLC, Grand Rapids, MI, USA.
3
Beryllium, 7869 NE Day Rd. West, Bainbridge Island, WA 98110, USA.
4
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA.
5
Tetra Discovery Partners LLC, Grand Rapids, MI, USA; Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA. Electronic address: mark@tetradiscovery.com.

Abstract

In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.

KEYWORDS:

Crystallography; PDE4 inhibitor; PDE4B; PDE4D; Triazine

PMID:
24998378
PMCID:
PMC4142572
DOI:
10.1016/j.bmcl.2014.06.002
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center