Merck KGaA

Selective Autotaxin Inhibitors: a new therapeutic option for CNS diseases, psychiatric and eating disorders

Posted by Merck KGaAResponsive · Innovative Products and Technologies · Germany

Summary of the technology

Recent findings (IP protected) reveal a substantial role for Autotaxin (ATX) in context of several biological effects at the synaptic cleft which are indicating a critical role in CNS disorders. This opens new therapeutic potential for ATX inhibitors.

Merck KGaA Darmstadt, Germany has developed and patented the results of its intense R&D activities for the identification of small organic molecules as selective inhibitors of Autotaxin.

Based upon the rational screening cascade established, compounds have been identified and characterized with regard to their specific in vitro, cellular and in vivo activities.

The package includes access to the IP, experimental results, and materials.

Merck KGaA

Description of the technology

Based upon the rational screening cascade established, selective inhibitors of ATX have been identified and characterized with regard to their specific in vitro, cellular and in vivo activities. Merck has patented the results of these intense R&D activities.


In collaboration with the group of Robert Nitsch and Johannes Vogt, Merck has also filed a patent on the use of ATX inhibitors for the treatment of CNS disorders and psychiatric diseases.
The package offered includes access to the patents, experimental results, related know-how and materials.

Abstract

Recent findings (IP protected) reveal a substantial role for Autotaxin (ATX) in context of several biological effects at the synaptic cleft which are indicating a critical role in CNS disorders. This opens new therapeutic potential for ATX inhibitors.

Biological Rationale and Therapeutic Use

Autotaxin is a secreted enzyme that functions as a lysophospholipase D to generate bioactive phospholipid lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). LPA binds to several G protein-coupled receptors (GPCRs) and plays a role in a number of physiological processes. In the brain, LPA stimulates excitatory transmission at the glutamatergic synapse (Trimbuch et al., Cell 2009). ATX is released from glial cells engulfing these synaptic sites and fueling local LPA concentrations. Thus,
ATX-inhibition is a versatile strategy to target disorders with hyperexcitatory pathophysiology (Vogt et al., EMBO Mol Med 2015).


Robert Nitsch and Johannes Vogt (University of Mainz) have discovered that ATX inhibitors reduced stress-related impact in psychiatric disorders, food intake and infarct size after stroke in mice:

 

  1. ATX inhibition reverses pathophysiological effects (e.g. pre-pulse inhibition [PPI], which is regarded as an endophenotype of psychiatric disorders) resulting from hyperexcitation due to altered phospholipid signaling as well as in a ketamine model of schizophrenia. Pilot studies in humans carrying a recently reported loss-offunction SNP in a molecule controlling LPA signaling (R345T/mutPRG-1) affecting ~5 million European and US citizens in a monoallelic variant point to an altered PPI correlate (P50 event related potential) in human mutation carriers. A mouse model carrying this human mutation showed hyperxcitation at the synapse and an altered PPI, which could be treated by ATX-inhibition.
  2. ATX-inhibition reduced increased food-intake of mice after overnight food-deprivation and prevented food-deprivation reduced novel object recognition behavior. However, other behavioral features (e.g. open field locomotion) were not affected by ATX-inhibition, pointing to a specific effect for foodintake. Importantly, excessive food-intake and related behaviors were not entirely blocked, but were significantly diminished rendering ATX-inhibition a therapeutic option for the control of hyperexessive food-intake.
  3. In a mouse model of ischemic stroke (middle cerebral artery occlusion, MCAO), ATX-inhibition was effective in reducing the infarct size and significantly decreased stroke-related altered behaviors.
  4. ATX-inhibition showed no detectable effect in normal mice, neither on the electrophysiological (cellular) level, nor on systems brain function in vivo, nor on behaviors. Evidently, only pathophysiological hyperxcitatory states are targeted by ATX-inhibition. Intervention into bioactive lipid signaling by ATX-inhibition is thus a promising and specific strategy to interfere with symptoms in CNS disorders and psychiatric diseases due to hyperexcitatory states (Vogt 2015).

 

Figure 1: Inhibition of Autotaxin: Role in synaptic LPA signaling. Adapted from Trimbuch et al., Cell 2009 138:1222-35 and Vogt et al., EMBO Mol Med 2015 8:25-38

 

Patent Details

Merck has obtained international patent protection in the field of autotaxin inhibitors.

WO2009046841 (granted in key markets)

Figure 2 :
The invention relates to compounds of formula (I) in which R1, R2, R3, D, G, Q and W can be defined as follows:

  • R1 = arom. heterocycle with provisos;
  • D = C, S; G = N, C; R2 = missing (sic), H, aryl with provisos;
  • Q = alkylene with provisos;
  • R3 = H, halo, CN, etc.;
  • W = aryl, Het.
  • Cpds. (I) are claimed useful as antitumor agents.
  • 184 cpds, 1 g available for one cpd.

Their pharmaceutically acceptable salts and formulations were prepared. e.g.

WO2011044978 (granted in key markets)

 

Figure 3: The invention relates to sulfoxide derivatives of formula (II) and to the pharmaceutically usable salts, solvates, enantiomers, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios for treating tumors.

13 cpds, 5 g available for one cpd.
e.g.

WO2010115491 (granted in key markets)

 

Figure 4: The invention relates to piperidine and piperazine derivatives of formula (III), which are autotaxin inhibitors and which are useful in the treatment and prophylaxis of cancers and other autotaxin-mediated diseases. 189 cpds, 50 g available for 1 cpd.
e.g.

CNS disorders patent application PCT/EP2016/001750 filed
The application will be disclosed under CDA.

In addition to, and independent of, any compound protection the medical use application will provide for exclusivity in this medical field until 2036.

 

Terms

Merck is seeking partners, who are interested in acquiring this technology.

  • Fast track partnering.
  • Signing fee: 150,000 Euros.
  • Transfer of entire IP package, experimental report and different compounds for the patent applications filed (mg-amount for most compounds, 1, 5 or 50g for 1 selected compound each; transfer costs to be covered by licensee).
  • Merck retains a non-exclusive, non-transferable, cost free global license on compounds covered by the transferred patents except for 1 compound to be nominated by the licensee at its own discretion within 10 years.
  • Milestone payment for first marketing approval in first country: 1 million Euros
  • Royalties on net sales: 1 %.

Robert Nitsch and his team are highly interested to support the further development of Autotaxin inhibitors for the treatment of CNS disorders. The terms concerning the transfer of technology and rights to the IP, and further joint development (if desired) are to be negotiated.

 

Technology Owner

Merck KGaA

Large Enterprise

Related keywords

  • Pharmaceutics
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  • Medical Research
  • Pharmaceutical Products / Drugs
  • Biology / Biotechnology
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  • In-vitro diagnostics
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About Merck KGaA

Large Enterprise from Germany

Merck KGaA, Darmstadt, Germany is a leading company for innovative and top-quality high-tech products in healthcare, life science and performance materials. Around 39,000 employees work in 65 countries to improve the quality of life for patients, to further the success of our customers and to help meet global challenges.

Legal Disclamer

There are two different, unaffiliated companies that use the name MERCK. Merck KGaA, Darmstadt, Germany, which operates this website, uses the firm name “Merck KGaA, Darmstadt, Germany,” in the United States and Canada, and also uses “EMD Serono” in biopharma, “MilliporeSigma” in life science and “EMD Performance Materials” in materials business. The other company, Merck & Co., Inc. holds the rights in the trademark MERCK in the United States and Canada. Merck & Co. is not affiliated with or related to Merck KGaA, Darmstadt, Germany, which owns the MERCK trademark in all other countries of the world. To reflect such fact and to avoid any confusion, certain logos, terms and business descriptions of the publications on this website have been substituted or modified, such as by referring to “Merck KGaA, Darmstadt, Germany” instead of “Merck” standing alone. Publications on this webpage, therefore, slightly deviate from the otherwise identical versions accessible outside the United States and Canada.

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