A series of substituted 3,6-diphenyl-7H-[1,2,4] triazolo[3,4-b] [1,3,4] thiadiazines that act as inhibitors of PDE4

Phosphodiesterase 4 (PDE4) is a major cAMP-metabolizing enzyme found in immune and inflammatory cells, airway smooth muscle, and pulmonary nerves. It plays a significant role within the inflammatory responses associated with asthma and chronic obstructive pulmonary disease (COPD) and its modulation has been linked to memory enhancement and depression. Due to its widespread therapeutic potential, PDE4 inhibitors are highly sought after agents for treating numerous disease states. While several PDE4 inhibitors have already advanced into clinical settings, unfavorable side effects including emesis, nausea, and abdominal pain emphasize the need for novel chemotypes with potent and selective PDE4 inhibition.

 

This technology describes a series of substituted 3,6-diphenyl-7H-[1,2,4] triazolo[3,4-b] [1,3,4] thiadiazines that act as inhibitors of  PDE4. This core structure represents a novel chemotype within extensive classes of PDE4 inhibitors and the structure activity relationships of these PDE4 inhibitors identify key binding sites and substitutions critical to the functionality for potent PDE4 inhibition. Selectivity of this novel chemotype shows weak inhibitory potency against nine PDE isoforms excluding PDE4 and strong inhibitory potency against PDE4A, PDE4B, and PDE4D. In a selectivity comparison study, the novel chemotype performs better than the PDE4 inhibitor in clinical development. Subtype-selective PDE4 inhibitors are becoming increasingly more important as new research shows that independent PDE isoforms have differential effects on cells.

 

Applications: 

Treatment of numerous diseases associated with PDE4 including asthma, COPD, inflammatory bowel disease, and other anti-inflammatory diseases with other possible treatments including depression and psychosis.

 

Publication: 

AP Skoumbourdis et al. Identification of a potent new chemotype for the selective inhibition of PDE4. Bioorg Med Chem Lett. 2008 Feb 15;18(4):1297-1303.  [PubMed abs]

Preclinical

U.S. Provisional Application No. 61/020,079 filed 09 Jan 2008 (HHS Reference No. E-055-2008/0-US-01)

 

Inventors: 

Craig J. Thomas et al. (NHGRI)

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