PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Glycine Transporter 1 Inhibitors and the Promise of a New Schizophrenia Therapy Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
4,5- Dihydropyrazole Derivatives, Pharmaceutical Compositions Containing Them, and Their Use in Therapy
Patent Application Number: US 2016/0075691 A1 Priority Application: US 62/049,231
Publication date: Priority date:
March 17, 2016 September 11, 2014
Inventors:
Amberg, W.; Brewer, J.; Hutchins, C.; Lange, U.; Lao, Y.; Li, H.-Q.; Pohlki, F.; Vasudevan, A.; Wang, Y.; Zhao, H.
Applicants:
AbbVie Deutschland GMBH & Co. KG, Wiesbaden (DE) AbbVie Inc., North Chicago, IL, USA
Disease Area:
Schizophrenia
Summary:
The present invention relates to 4,5-dihydropyrazole derivatives represented generally by formula (I). These compounds are GlyT1
Biological Target:
Glycine transporter-1 (GlyT1)
inhibitors and may be beneficial in the treatment of symptoms of schizophrenia patients. Glutamate is the conjugate base of glutamic acid (2-aminopentanedioic acid). Glutamate is abundant in the human nervous system and in the brain. It is a very important excitatory neurotransmitter that plays a major role in neural activation. It acts as the brain’s main excitatory neurotransmitter, and it is also used as the precursor for the biosynthesis of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. They are responsible for the glutamate-mediated postsynaptic excitation of neural cells and are important for neural communication, memory formation, learning, and regulation. One of the glutamate receptors is the N-methyl-D-aspartate (NMDA) receptor. It was named because the agonist molecule N-methyl-D-aspartate can bind to it selectively but not to any other glutamate receptors. NMDA receptor is activated by glutamate in addition to glycine as a coagonist. Its activation allows positively charged ions to flow through the cell membrane. The NMDA receptor is very important for controlling synaptic plasticity and memory function. Many of the central nervous system (CNS) disorders are caused by dysfunction of the glutamatergic pathways. These include schizophrenia, cognitive deficits, dementia, Parkinson disease, Alzheimer disease, bipolar disorder, and other disorders. Schizophrenia is a complex disease that affects patients’ thinking, feelings, and actions. It affects about 1% of the world population and requires lifelong therapy. A large number of animal models studies support what is known as the NMDA hypofunction hypothesis of schizophrenia. The hypothesis focuses on the hypofunction of the NMDA glutamate transmitter system as a cause of schizophrenia, and therefore, the modulation of that system may potentially provide a promising treatment for schizophrenia. Researchers have identified two specific glycine transporters, GlyTl and GlyT2. They belong to the Na/Cl-dependent family of neurotransmitter transporters, which also includes taurine, GABA, proline, monoamines, and orphan transporters. GlyT1 and GlyT2 have only about 50% similarities at the amino acid level. GlyT2 is expressed in spinal cord, brainstem, and cerebellum, while GlyT1 is expressed in these regions as well as in the forebrain areas such as cortex, hippocampus, septum, and thalamus. Rat studies have shown that GlyT2 is expressed by glycinergic nerve endings in rat spinal cord, whereas GlyT1 appears to be preferentially expressed by glial cells. These studies suggest that GlyT2 is predominantly responsible for glycine uptake at glycinergic synapses, whereas GlyT1 is involved in monitoring glycine concentration in the vicinity of NMDA receptor expressing synapses. Other recent rat studies have demonstrated that inhibition of GlyT1 potentiates NMDA receptor activity and affects NMDA receptor-dependent long-term potentiation. Molecular cloning has identified three variants of GlyTl, named GlyT-1a, GlyT-1b, and GlyT-1c. They differ in their N-terminal regions and display unique distributions in the brain and peripheral tissues. The function of the NMDA receptor can be modulated by varying the levels of the glycine coagonist. The inhibition of GlyT1 slows the process of removal of glycine from the synapse, which elevates the level of synaptic glycine. The increase in the synaptic concentration of glycine does not produce an activation of NMDA receptors in the absence of glutamate and that maintains the activity-dependent activation of the NMDA receptor. Since high affinity transport mechanisms maintain tight levels of the synaptic glutamate, an increased activation of the glycine site will only enhance the NMDA component of activated synapses.
Received:
r XXXX American Chemical Society
A
May 1, 2016
dx.doi.org/10.1021/acsmedchemlett.6b00183 | ACS Med. Chem. Lett. XXXX, XXX, 000–000
ACS Medicinal Chemistry Letters Summary (continued):
PATENT HIGHLIGHT
The accumulated knowledge about the physiological effects of GlyTl in the forebrain regions together with the clinical reports showing some beneficial effects of the known GlyT1 inhibitor sarcosine (N-methylglycine) in improving schizophrenia symptoms in patients suggest that selective GlyTl inhibitors may provide a new effective and promising therapy for this disease. GlyTl inhibitors may also be useful in treating a variety of other neurologic and psychiatric disorders. The inventors reported that several glycine transporter inhibitors are already known in the art, but there is still a need for additional GlyT1 inhibitors such as the compounds of formula (I) described in this patent application, which combine high stability and high affinity with favorable efflux properties in addition to displaying good oral bioavailability.
Important Compound Classes:
Key Structures:
The inventors described the synthesis and structures of 30 compounds of formula (I) including the following representative examples:
Biological Assay:
1. [3H]-Glycine Uptake into Recombinant CHO Cells Expressing Human GlyTl 2. Radioligand Binding Assays Using Recombinant CHO Cell Membranes Expressing Human GlyT1
Biological Data:
Recent Review Articles:
The following results were obtained from testing the above representative examples using assay 2:
(1.) Singer, P.; Dubroqua, S.; Yee, B. K. Curr. Pharm. Des. 2015, 21 (26), 3771 3787. (2.) Harvey, R. J.; Yee, B. K. Nat. Rev. Drug Discovery 2013, 12 (11), 866 885. (3.) Chue, P. Curr. Pharm. Des. 2013, 19 (7), 1311 1320.
B
dx.doi.org/10.1021/acsmedchemlett.6b00183 |ACS Med. Chem. Lett. XXXX, XXX, 000–000
ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
’ AUTHOR INFORMATION Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
C
dx.doi.org/10.1021/acsmedchemlett.6b00183 |ACS Med. Chem. Lett. XXXX, XXX, 000–000
