Research Project
9355226
The prevalence of major depression is staggering with around 20% of people experiencing depression at some point in their lives. The market for antidepressant drugs is expected to grow at a CAGR of 3.2% to US $10.9 billion by 2018. The World Health Organization predicts that by 2020, depression will rival heart disease as the health disorder with the highest disease burden in the world. The company proposes to develop a new treatment for major depressive disorder based on inhibition of phosphodiesterase 4B (PDE4B). Uniquely, the Tetra drug will address inflammation as a contributor to depression. This is a new mechanism of action for an antidepressant drug which should prove complimentary to current therapeutics. The company estimates that 10-20% of patients with depression have co-morbid inflammation and will be ideal candidates for the Tetra drug. Addressing inflammation will target currently untreatable patients, such as those receiving interferon-? (IFN?) for viral illness, depressed patients with co- morbid psoriasis, inflammatory bowel disease, traumatic brain injury, or post-traumatic stress disorder. Given the limitations of current treatments, there is a need for new medications with novel mechanisms of action. During the course of the SAR campaign funded by the Phase II SBIR, Tetra synthesized over 400 compounds representing multiple chemical series. The Tetra compounds are allosteric inhibitors of PDE4B that act by closing the CR3 C-terminal regulatory domain across the active site. As CR3 is present in all isoforms of PDE4B, Tetra compounds have similar potency against dimeric, long forms as well as monomeric, short forms of the enzyme. Inhibition of the monomeric, short forms of PDE4B is needed for anti-inflammatory benefit. The binding mode of Tetra PDE4B inhibitors is supported by multiple co-crystal structures of inhibitors bound to PDE4B which are used to guide structure-based drug design. The best compounds to date are highly potent (PDE4B IC50 < 10 nM), up to 300 fold selective against other PDE4 enzymes, and distribute to brain (brain/plasma ratio up to 6.7). Lead compounds have antidepressant-like benefit in rodent models (Minimum Effective Dose = 0.01-0.1 mg/kg) and reduce TNF expression after brain injury. The Phase IIB SBIR project will complete chemical optimization of a PDE4B inhibitor for use in human with the goal of developing a drug for the treatment of major depression.
