We have developed a platform to identify and advance diverse classes of small molecules to selectively inhibit the sodium-potassium chloride cotransporter (NKCC1) and other therapeutic targets relevant to treating central nervous system disorders.
NKCC1 mediates the coupled movement of chloride with potassium and sodium across the cell membrane with essential roles in physiological processes, including modulating neuronal excitability. High NKCC1 activity contributes to maintaining an elevated intracellular chloride concentration such that GABA (γ-aminobutyric acid), the principal inhibitory neurotransmitter in mature neurons under physiological conditions, stimulates chloride efflux and produces depolarizing and excitatory outward currents in immature neurons.
The activity of NKCC1 increases in several pathological conditions; this is why NKCC1 inhibition shows great potential in treating idiopathic and secondary forms of autisms (autism spectrum disorder -ASD-), refractory epilepsy, and other neurological conditions.
Our purpose is to provide a therapeutic solution to individuals suffering from neurological conditions and provide their families with the support they need.
Selective Cation Chloride Cotransporter Inhibitors
IAMA-6 is an early-stage compound that has shown encouraging in vitro and in vivo proof of concept results in idiopathic and secondary forms of autism. The compound is designed to directly target and inhibit NKCC1, a sodium-potassium chloride co-transporter responsible for maintaining chloride homeostasis in neurons.
"Pharmacological tools to target NKCC1 in brain disorders"
Trends in Pharmacological Sciences (Cell Press) 2021, 42, 12, 1009-1034
C. Portioli, M. J. Ruiz Munevar, M. De Vivo, L. Cancedda
"Cation-coupled chloride cotransporters: chemical insights and disease implications"
Trends in Chemistry (Cell Press), 2021, 3, 10, 832–849
M. Borgogno, A. Savardi, J. Manigrasso, A. Turci, C. Portioli, G. Ottonello, S. M. Bertozzi, A. Armirotti, A. Contestabile, L. Cancedda, M. De Vivo
"Design, synthesis, in vitro and in vivo characterization of selective NKCC1 inhibitors for the treatment of core symptoms in Down syndrome and other brain disorders”
Journal of Medicinal Chemistry 2021, 64, 14, 10203–10229
A. Savardi, M Borgogno, R. Narducci, G. La Sala, J. Ortega, M. Summa, A. Armirotti, R. Bertorelli, A. Contestabile, M. De Vivo, L Cancedda
"Discovery of a small molecule drug candidate for selective NKCC1 inhibition in brain disorders"
Chem (Cell Press) 2020, 6, 1–24
L. Riccardi, V. Genna, M. De Vivo
"Metal-ligand interactions in drug design"
Nature Reviews Chemistry, 2018, 2, 100–112
G. Deidda, M. Parrini, S. Naskar, I. F. Bozarth, A. Contestabile, L. Cancedda
"Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome”
Nature Medicine, 2015, 21, 318–326