Tetra is developing a platform of drug products to treat cognitive impairment. Tetra drugs target a family of related enzymes known as Type 4 phosphodiesterases (PDE4).
The lead drug targeting PDE4D 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.
Tetra’s BPN14770 cognition drug is a first-in-class, negative allosteric modulator of phosphodiesterase-4D (PDE4D). Human PDE4 enzymes exist in “on” and “off” states. PDE4D is switched “on” when it is phosphorylated by cAMP-dependent protein kinase A. Switching the enzyme “on” opens a key regulatory domain known as UCR2 and allows cAMP to bind. The enzyme is switched “off” by closing the regulatory domain, although even when switched “off,” the PDE4 enzyme retains basal activity. Safety and tolerability are improved because the enzyme is not completely inhibited.
The Tetra team was the first to describe the crystal structure of the UCR2 regulatory domain and the first to design drugs that preferentially inhibit the enzyme when it is in the “on” state by binding the UCR2 regulatory domain. The Tetra team has overcome the problem of earlier drugs which cause emesis by designing compounds that preferentially inhibit PDE4D when it is in the “on” state rather than the “off” state. Such compounds improve learning and memory in multiple animal models without causing nausea.
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.