Product description

         DT1133

DT1133 and analogs are NCEs with adenosine A2A-antagonist potency originally discovered with DTect-All™ technology. These molecules belong to a chemical family distinct from the known xanthines or furan-containing A2A-antagonists currently in development and known to present metabolism issues. DT1133-series was shown to be selective for A2A–receptor against a panel of more than 70 targets and two distinct selectivity profiles were obtained with regard to A1 adenosine receptor. This series of ligands shows no flag in early ADME-Tox (hERG, AMES, CYP inhibition), excellent oral bioavailabilities in rodents and no clinical sign in a 14-day rat toxicology study. DT1133 & analogs display anti-Parkinsonian activities in animal models such as the haloperidol-induced catalepsy and the reserpine-induced dyskinesia in both rats and mice after oral administration. It is protected by a composition of matter patent filed in 2009. A candidate, ready to enter regulatory preclinical development was nominated in this program.

         DT1687

Metabotropic glutamate receptors 4 (mGluR4) is an attractive but challenging therapeutic target with high potential for indications such as Parkinson’s disease or anxiety. Its modulation by positive allosteric modulators (PAMs) has been shown to produce symptomatic benefits and to exert neuroprotection in animal models of chronic degenerative conditions. Domain Therapeutics and Prestwick Chemical have discovered and developed, in the course of a collaborative project called ARAMIS, optimized leads with nanomolar PAM potency on mGluR4 and oral activity in several models of Parkinson’s disease. This program is partnered with Merck-Serono and collaboration is ongoing for the selection of preclinical candidates.

         DT2228

Metabotropic glutamate receptors 2 (mGluR2) negative allosteric modulators (NAMs) represent a novel promising approach for the treatment of Alzheimer’s disease (AD) or Depression. Indeed, it was recently shown that mGluR2 NAMs exert cognitive improvements in animal models of the disease and that mGluR2 inhibition can alter neuronal degeneration in AD. Using DTect-All™ platform, NCEs with mGluR2 NAM properties were identified and optimized to the lead stage. This family of molecules, represented by DT2228, exerts nanomolar NAM activity and presents a good early ADME-tox profile with excellent oral bioavailability and brain penetration. The program is currently at the lead optimization phase.

         DT2208

Starting from a mGluR2/3 NAM series, Domain’s chemists were able to perform a switch of functional activity to obtain novel mGluR3 PAM and patentable chemical structures. Similar switches were previously described by Domain and are now considered as common features of GPCR allosteric modulators. These mGluR3 PAMs are NCEs showing selectivity vs. the close mGluR2 and sub-micromolar potency. mGluR3 PAM represents a new mechanism of action for Parkinson’s Disease treatment with strong potential for neuroprotection through the production of TGF-beta and GDNF. mGluR3-mediated neuroprotection has been shown in experimental animal models of Parkinson’s disease and the GDNF-mediated neuroprotection has been demonstrated in clinic. The mGluR3 PAM series is currently at the hit-to-lead optimization phase.

         DTXXXX

Glucagon-Like Peptide 1 Receptor (GLP-1R) is a family II GPCR targeted by the peptidic agonist Exenatide for type II diabetes treatment. Using DTect-All™ technology, Domain is focusing efforts towards identification of small molecules with positive allosteric modulator (PAM) or ago-allosteric properties on GLP-1R. This is a challenging project because, to date, only a few small molecule ligands have been identified for members of this GPCR family.