Thursday, June 18, 2015

Drugs in Clinical Pipeline: ADX-88178

ADX-88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiazol-2-amine] is a small molecule positive allosteric modulator (PAM) of metabotropic glutamate receptor subtype 4 (mGluR4; GRM4). The molecule is selective for mGluR4, orally available, brain penetrant and has the potential to ameliorate Parkinsonian symptoms. Addex has reported ADX88178 as a novel mGluR4 PAM and demonstrated its efficacy in several different rodent models of Parkinson’s disease [1].

The activity of ADX88178 is as follows:

EC50 (human mGluR4, FLIPR assay) = 3.5 ± 0.3 nM
EC50 (rat mGluR4, FLIPR assay) = 9.1 ± 1.0 nM
Ki (human mGluR4, Binding assay) = 39 nM

Common Name: ADX-88178
Synonyms:  ADX88178; ADX 88178; ADX-88178
IUPAC Name: 5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiazol-2-amine
CAS Number: 1235318-89-4
Mechanism of Action: Metabotropic glutamate receptor (mGluR) modulator
Indication: Treatment for Parkinson’s disease; Treatment for PD
Development Stage: Preclinical
Company: Addex Therapeutics Ltd.

Parkinson’s disease or PD (also known as idiopathic, or primary parkinsonism, hypokinetic rigid syndrome (HRS) or paralysis agitans) is a degenerative disorder of the central nervous system mainly affecting the motor system. The motor symptoms of Parkinson’s disease result from the death of dopamine-generating cells in the substantia nigra (SN, a region in the mid brain). As a consequence of the depletion of dopamine, a series of movement disorders appear, including bradykinesia, akinesia, tremor, gait disorders and problems with balance. These motor disturbances form the hallmark of Parkinson’s disease, although there are many other non-motor symptoms also that are associated with the disease, such as sensory, sleep and emotional problems. PD is more common in older people, with most cases occurring after the age of 50. When the symptoms are observed in young adults, it is called young onset PD (YOPD). In the early course of the disease, symptoms can be effectively treated by dopamine replacement or augmentation with the use of dopamine D2 receptor agonists, such as levodopa or monoamine oxidase B inhibitors. But, as the disease progresses these agents become less effective in controlling motor symptoms. Also, the use of these agents is limited by the emergence of adverse effects including dopamine agonist-induced dyskinesias. Therefore, activation of metabotropic glutamate receptor 4 (mGluR4) has been proposed as a potential therapeutic approach to treat Parkinson’s disease [2, 3, 4].

The metabotropic glutamate receptor 4 (mGlu4) belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Gai/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in transmitter release from presynaptic terminals. MGlu4 is currently receiving much attention based primarily upon its unique distribution in key brain region involved in many CNS disorders. MGlu4 PAM is emerging as a promising target for the treatment of motor and non-motor symptoms as well as a disease-modifying agent in Parkinson`s disease through a non-dopaminergic approach.

Symptoms of Parkinson’s disease are believed to be due to progressive death of dopaminergic. Reduction in dopaminergic neurotransmission leads to an imbalance in the direct and indirect output pathways of the basal ganglia. Reduction of transmission at the inhibitory GABAergic striato-pallidal synapse in the indirect pathway is believed to result in alleviation of these symptoms. mGluR4 is abundant in striato-pallidal synapses. Its localization suggests it functions as a presynaptic heteroreceptor on GABAergic neurons, suggesting in turn that selective activation or positive modulation of mGluR4 would decrease GABA release in this synapse, thereby decreasing output of the indirect pathway and reducing or eliminating the PD symptoms.

In vitro properties of ADX88178 were evaluated by monitoring calcium mobilization in HEK293 cell lines modified to express human and rat mGluR4. ADX88178 was also evaluated in a radioligand binding assay with human mGluR4 receptors obtained from membranes from the HEK293 cell line. The compound completely displaced the specific binding of [3H]PAM2, a structurally distinct compound in this assay. When investigated for its selectivity for mGluR4, ADX88178 exhibited no effect on mGluR1, 2, 3, 5, 7 or GABAB at concentrations upto 30 uM. Agonist activity at mGluR6 was detected with an EC50 value greater than10 uM, while the compound acted as a PAM at mGluR8 with an EC50 of 2.2 uM. The compound was found to be inactive at 10 uM when screened against other receptors, transporters, enzymes and ion channels in the Cerep panel, except human adenosine A1 and A3 [1].

ADX88178 reverses haloperidol induced catalepsy (HIC) in rats at 3 and 10 mg/kg after oral administration. More importantly, the combination of ADX88178 (3, 10 and 30 mg/Kg, p.o.) with a low dose of L-DOPA enabled a robust, dose-dependent reversal of the forelimb akinesia deficit induced to a bilateral 6-OHDA lesion of the striatum in rats. In addition, co-administration of ADX88178 (10 mg/kg, p.o.) did not worsen dyskinesia induced by L-DOPA in rats subjected to a unilateral 6-OHDA lesion of the medial forebrain bundle. This is consistent with an L-DOPA sparing action that may prove to be therapeutically useful for the management of motor symptoms of PD.

1. Le Poul, E.; et. al. A potent and selective metabotropic glutamate receptor 4 positive allosteric modulator improves movement in rodent models of Parkinson’s disease. J Pharmacol Exp Ther 201243(1), 167-177.
2. Marino, M. J.; et. al. Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson’s disease treatment. Proc Natl Acad Sci USA 2003100(23), 13668-13673.
3. Marino, M. J.; et. al. Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol 20066(1), 98-102.
4. Duty, S. Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson’s disease. Br J Pharmacol 2010161(2), 271-287.