Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center

Yvonne R Freund; Tsutomu Akama; M R K Alley; Joana Antunes; Chen Dong; Kurt Jarnagin; Richard Kimura; James A Nieman; Kirk R Maples; Jacob J Plattner; Fernando Rock; Rashmi Sharma; Rajeshwar Singh; Virginia Sanders; Yasheen Zhou

doi:10.1016/j.febslet.2012.07.058

Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center

FEBS Lett. 2012 Sep 21;586(19):3410-4. doi: 10.1016/j.febslet.2012.07.058. Epub 2012 Jul 25.

Authors

Yvonne R Freund¹, Tsutomu Akama, M R K Alley, Joana Antunes, Chen Dong, Kurt Jarnagin, Richard Kimura, James A Nieman, Kirk R Maples, Jacob J Plattner, Fernando Rock, Rashmi Sharma, Rajeshwar Singh, Virginia Sanders, Yasheen Zhou

Affiliation

¹ Anacor Pharmaceuticals Inc., Palo Alto, CA 94303, USA. yfreund@anacor.com

PMID: 22841723
DOI: 10.1016/j.febslet.2012.07.058

Abstract

We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors.

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Binding, Competitive
Boron Compounds / chemistry*
Boron Compounds / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Catalytic Domain
Crystallography, X-Ray
Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry*
Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
Cytokines / biosynthesis
Humans
In Vitro Techniques
Isoenzymes / antagonists & inhibitors
Isoenzymes / chemistry
Isoenzymes / genetics
Isoenzymes / metabolism
Kinetics
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / immunology
Metals / chemistry
Models, Molecular
Phosphodiesterase Inhibitors / chemistry*
Phosphodiesterase Inhibitors / pharmacology*
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism

Substances

Anti-Inflammatory Agents, Non-Steroidal
Boron Compounds
Bridged Bicyclo Compounds, Heterocyclic
Cytokines
Isoenzymes
Metals
Phosphodiesterase Inhibitors
Recombinant Proteins
Cyclic Nucleotide Phosphodiesterases, Type 4
PDE4B protein, human
crisaborole