Clinical Candidate


Drug testing begins with extensive laboratory research which can involve years of experiments in animals and human cells. If the initial tests are successful, human testing of study drugs can begin and is typically conducted in four phases where each phase is considered a separate trial.

Our team has synthesized more than 150 quinoline analogues and tested them in vitro for cytoprotective effects. Two families of follow-up compounds were also synthesized.

Among them, preclinical studies proved safety, good stability, and acceptable oral bioavailability for Q134R. Phase I/A study was successfully finished in 2017, and a 2-years efficacy study has started in aged dogs in the USA.

The Phase I/A first-in-man clinical trial for Q134R has been granted by the Hungarian competent authority, OGYÉI. The study was conducted with 20 healthy volunteers, in a single blind arrangement. Our drug candidate proved to be safe in the dose range checked. Only mild to moderate adverse effects (e.g. headache) were detected both in the treated and the placebo groups.

Based on in vitro and in vivo pharmacology results, the advantageous ADME-T properties on animal studies and the good safety and pharmacokinetic properties on Phase I human studies, Q134R seems to be a promising drug candidate with multiple and original new mechanisms of action for the treatment of neurodegenerative diseases.

APERUS intends to perform a detailed human safety Phase I/B1 and I/B2 study with single and repeated doses, and a long-term dog safety and efficacy study with biomarker research in our collaborator’s facility, the University of Kentucky, USA. After Phase I/B, we intend to enter Phase II/A, which goal is to determine the ideal doses to be administered and the potential biomarkers and to investigate whether the drug candidate shows the expected and desired effects. In Phase II/B, tests are to be carried out with larger groups of patients. Besides efficacy, disease markers are also investigated while safety and tolerability are further assessed. As part of Phase II, the goal will be to clinically confirm the cognitive enhancing characteristic of Q134R, applying the well-known and accepted pharmacologic model of induced dementia (scopolamine challenge), paired with sensitive neuropsychological tests on elderly volunteers.

The pathological conditions of the brain of patients with Alzheimer’s disease are innately very complex. Therefore, our research process was based on a multiple target approach.

Q134R restores memory impairment caused by scopolamine or Abeta oligomers, by modulation of the GABAA-gated Cl- channels, specific for extrasynaptic signalling in neuronal cells. The compound prevented hippocampal neuronal death against oligomeric Aβ toxicity in vitro and in vivo (4 mg/kg oral dose resulted in complete recovery of synaptic proteins and short-term memory in mice). Q134R recovered cognition in scopolamine-induced mouse amnesia model, while it had no effect in GABA-Ag KO mice. One and three weeks long daily treatment of 2xTg (PSE/APP) mice resulted in normalized Y-maze scores. Positive effects of Q134R on synaptic function and strength were determined by electrophysiological recordings.

Q134R is a strong cytoprotective agent. At nanomolar concentration, it protects neuronal cells against neuronal death induced by reactive oxygen species (ROS) and Abeta (amyloid beta) oligomers, as well as restores mitochondrial functioning. The compound inhibits HIF1α protein degradation resulting in activation of cytoprotective genes. In cellular assays it induces the expression of genes whose protein products combat oxidative-stress, such as hemoxygenase-1 (HMOX-1), gluthatione peroxidase-1 (GPX-1), superoxide dismutase-1 (SOD-1) and erythropoietin (EPO) in a concentration dependent manner. Similar gene induction effects could be confirmed in the cortex and hippocampus of orally treated mice. Pharmacological induction of these proteins have been implicated in effective therapy of diverse set of neurological diseases, including traumatic brain injury, bipolar depression, schizophrenia, epilepsy and neurodegenerative diseases (Alzheimer’s disease, Parkinson disease and Huntington disease and amyotrophic lateral sclerosis).

Q134R has inhibitory effects on NFATs, a family of calcineurin- (CN) dependent transcription factors linked to multiple pathologic hallmarks that emerge during Alzheimer’s disease. Q134R inhibits both the induction of the NFAT transcriptional activity and caspase-3 enzyme activity, therefore prevents neuronal death by dual effects. Numerous studies show that inhibition of CN/NFAT signalling leads to beneficial effects on amyloid pathology, neuroinflammation, neuronal viability, synaptic physiology, and cognitive function in mouse models of Alzheimer’s disease. Although classic calcineurin-inhibiting drugs (e.g. tacrolimus or cyclosporine) have neuroprotective properties in animal models, their use in Alzheimer’s has been limited by adverse effects. Q134R inhibits NFAT signalling without affecting calcineurin itself, hence has no immunosuppressive side effects. As far as we know, there are no commercial NFAT inhibitors without expected immuno-suppression activity, especially with memory restoring effects. This makes Q134R a novel and a potential disease modifying drug with no expected side effects on the immune system.

Q134R prevents nuclear translocation of NFAT4 in hippocampal astrocytes of Alzheimer’s mice model. 12-15 mos 2xTg APP/PS1 mice were treated for 2 weeks orally with vehicle or Q134R (4mg/kg/2x daily). Arrowheads point to astrocyte nuclei. NFAT4 tends to fill astrocyte nuclei of vehicle treated but not Q134R-treated mice.


Detailed ADME-T was finished. The in vivo micronucleus test and the Ames test were negative. Cardiovascular effects, the functional observational battery in CNS and the effects on the respiratory function proved the safety of the molecule. Subchronic and chronic toxicity studies revealed no toxic side effects (52 weeks, non-GLP, in mice).


  1. Improved graft function following heart transplantation in rats;
  2. Cytoprotection in primary neural cells and cell lines exposed to a variety of insults;
  3. Significant increase in the survival rate of aging wild-type mice;
  4. Protection against scopolamine-induced memory deficits in wild-type mice;
  5. Protection against oligomeric amyloid beta induced memory deficits in wildtype mice;
  6. Reduction in amyloid load and improvement in Y maze performance in 1-year-old APP/PS1 mice after only 1 week of treatment;
  7. Agonistic behaviour on GABAA delta type Cl- channel (wild-type and GABA transgenic mouse brain slices with electrophysiology);
  8. Good safety and PK properties in Phase IA human study.