Tetra is developing a platform of drug products to treat cognitive impairment. The primary focus of our drug development effort is memory improvement. The way we store memories in our brain is by changing the connection between brain cells. These connections are known as synapses. Cognitive impairment occurs when synapses within the brain do not communicate properly at a cellular level. Cognitive problems occur when there is too much activity, or not enough—when neurons do not signal properly. Within brain cells, the substance which controls the way synapses communicate is cyclic AMP, or cAMP.
Tetra’s science builds on previous work by Nobel laureates that identified PDE4 (Phosphodiesterase 4) as a key enzyme that shapes proper cAMP signaling. Specifically, PDE4 limits the spread of cAMP so that spatial and temporal patterning of information is maintained.
The chemistry is a bit complicated. It turns out that PDE4 has 4 subtypes, and drug-induced inhibition of one (or more) of these subtypes can produce nausea or vomiting. To address such undesirable side-effects, Tetra has taken a different approach. Our compound targets only one of the PDE4 enzyme subtypes, and only at specific times of cellular activity. Tetra’s compound is designed to modulate, rather than completely inhibit, PDE4D. The result is that Tetra’s drug improves memory by prolonging cAMP activity. Safety and tolerability are improved because the enzyme is not completely inhibited.
Our lead drug targeting PDE4D, BPN14770, is being developed for treating cognitive impairment in Alzheimer’s disease or schizophrenia with potential applications for Huntington’s disease, Fragile X syndrome, autism, and major depression. Rather than addressing a specific chemical deficit or dysfunction in a specific neural circuit, targeting PDE4D has the potential to augment the fundamental processes underlying learning and memory in the human brain, thereby allowing compensatory brain mechanisms to improve function in the diseased brain.
MEDICINES FOR ALZHEIMER'S DISEASE | TETRA CO-INVESTIGATORS
NIH BLUEPRINT CONSULTANTS
|Vince Groppi, PhD / Pharmacology Lead||Donna Romero, PhD / Chemistry Lead|
|Marc Bailie, PhD / Safety and Toxicology Lead||Ron White, PhD / DMPK Lead|
|Jon Lawson, PhD / Process Chemistry||Jay Sisco, PhD / Formulation/Drug Product|
NIMH PET LIGAND CO-INVESTIGATORS
|Robert Innis MD PhD|
|Victor Pike PhD|
|Carlos Zarate MD|
MEDICINES FOR TRAUMATIC BRAIN INJURY
MEDICINES FOR SCHIZOPHRENIA & DEPRESSION
MEDICINES FOR FRAGILE X SYNDROME
SELECTED SCIENTIFIC PUBLICATIONS
- Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer’s disease. Gurney ME, D’Amato EC, Burgin AB.
Neurotherapeutics. 2015 Jan;12(1):49-56. doi: 10.1007/s13311-014-0309-7. PMID: 25371167
- Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Hagen TJ, Mo X, Burgin AB, Fox D 3rd, Zhang Z, Gurney ME. Bioorg Med Chem Lett. 2014 Aug 15;24(16):4031-4. doi: 10.1016/j.bmcl.2014.06.002. Epub 2014 Jun 12.
- Structural basis for the design of selective phosphodiesterase 4B inhibitors. Fox D 3rd, Burgin AB, Gurney ME.
Cell Signal. 2014 Mar;26(3):657-63. doi: 10.1016/j.cellsig.2013.12.003. Epub 2013 Dec 19.
- Small molecule allosteric modulators of phosphodiesterase 4. Gurney ME, Burgin AB, Magnusson OT, Stewart LJ.
Handb Exp Pharmacol. 2011;(204):167-92. doi: 10.1007/978-3-642-17969-3_7. Review. PMID: 21695640
- Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME. Nat Biotechnol. 2010 Jan;28(1):63-70. doi: 10.1038/nbt.1598. Epub 2009 Dec 27.