1. A non-human animal model for amyotrophic lateral sclerosis (ALS), comprising a rodent whose spinal cord motor neurons have a loss of TAR-DNA binding protein-43 (TDP-43) function and the rodent exhibits ALS-like symptoms.
2. The animal model of claim 1, wherein the rodent does not express TDP-43 protein in the spinal cord motor neurons.
3. The animal model of claim 2, wherein the rodent expresses TDP-43 protein in the cells other than the spinal cord motor neurons.
4. The animal model of claim 1, wherein the rodent’s TDP-43-encoding gene in the spinal cord motor neurons is inactivated.
5. The animal model of claim 1, wherein the rodent’s TDP-43-encoding gene in the spinal cord motor neurons is inactivated andor deleted.
6. The animal model of claim 1, wherein the rodent’s TDP-43-encoding gene in the spinal cord motor neurons comprises a homozygous disruption.
7. The animal model of claim 1, wherein the rodent expresses Cre recombinase in the spinal cord motor neurons, but not in other cells.
8. The animal model of claim 7, wherein the Cre recombinase is driven by HB9 promoter.
9. The animal model of claim 8, wherein the rodent comprises Lox P sites in its genome, and the cells other than the spinal cord motor neurons in the rodent comprise a TDP-43-encoding gene with a pair of Lox P sites.
10. The animal model of claim 1, wherein the rodent is phenotypically normal at birth and develops the ALS-like symptoms later.
11. The animal model of claim 1, wherein the animal model exhibits one or more than one of the following phenotypes:
(a) kyphosis;
(b) abnormal hind limb clasping;
(c) deficiency in motor coordination and motor learning ability;
(d) motor neuron loss in the spinal cord;
(e) astrocytosis in the spinal cord;
(f) weight loss compared with a control rodent; and
(g) accumulation of poly-ubiquitinated proteins in the spinal cord motor neurons.
12. The animal model of claim 1, wherein the exon 2 and exon 3 of TDP-43 -encoding gene in the rodent’s spinal cord motor neurons are deleted.
13. A tissue or a motor neuron which is isolated from the spinal cord of the animal model of claim 1.
14. The motor neuron of claim 13, comprising ubiquitinated protein aggregates and having no TDP-43 protein expression.
15. A method for identifying an agent with potential for treatment of a disease associated with a loss of TAR-DNA binding protein-43 (TDP-43) function in an animal, comprising:
administering the agent to a non-human animal model according to claim 1; and
determining whether the agent prevents andor inhibits at least one of the ALS-like symptoms; wherein prevention andor inhibition of the at least one of the ALS-like symptoms is indicative of an agent with potential for treatment of a disease associated with a loss of TDP-43 function.
16. The method of claim 15, wherein the rodent is a mouse
17. A method for identifying a candidate agent for treating, preventing andor inhibiting ALS associated with a loss-of-function of TDP-43, comprising:
administering the agent to a non-human animal model according to claim 1; and
determining whether the agent prevents andor inhibits at least one of the ALS-like symptoms; wherein prevention andor inhibition of the at least one of the ALS-like symptoms is indicative of a candidate agent for treating, preventing andor inhibiting ALS associated with a loss-of-function of TDP-43.
18. The animal model of claim 1, wherein the rodent is a mouse.
19. The animal model of claim 2, wherein the rodent’s spinal cord motor neurons comprise ubiquitinated protein aggregates.
20. The animal model of claim 1, wherein the rodent exhibits a loss of spinal cord motor neurons.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound according to formula I
wherein R1, R2, R3, R4 and R5 are H;
R6 is methoxymethyl;
A7 is C\u2014R7, A8 is N and A9 is C\u2014R9;
R7, R9, R10 and R11 are selected independently of each other from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy and OR12;
wherein R12 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C;
or a pharmaceutically acceptable salts thereof.
2. The compound according to claim 1, wherein R7, R10 and R11 are each H.
3. The compound according to claim 1, wherein R9 is C1-4alkoxy.
4. The compound according to claim 1, wherein R9 is OR12.
5. The compound according to claim 1 having a diastereomeric excess of at least 80%.
6. The compound according to claim 1 wherein the compound is selected from the group consisting of
46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid (R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl-amide;
47: (1S,2S)-N-(1R)-2-methoxy-1-6-(3R)-tetrahydrofuran-3-yloxy-3-pyridylethyl-2-phenyl-cyclopropanecarboxamide;
48: (1S,2S)-N-(1R)-2-methoxy-1-6-(3S)-tetrahydrofuran-3-yloxy-3-pyridylethyl-2-phenyl-cyclopropanecarboxamide; and
49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl-ethyl}-amide;
or a pharmaceutically acceptable salts thereof.
7. The compound according to claim 1, wherein the compound is
46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid (R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl-amide or a pharmaceutically acceptable salts thereof.
8. The compound according to claim 1, wherein the compound is
47: (1S,2S)-N-(1R)-2-methoxy-1-6-(3R)-tetrahydrofuran-3-yloxy-3-pyridylethyl-2-phenyl-cyclopropanecarboxamide or a pharmaceutically acceptable salts thereof.
9. The compound according to claim 1, wherein the compound is
48: (1S,2S)-N-(1R)-2-methoxy-1-6-(3S)-tetrahydrofuran-3-yloxy-3-pyridylethyl-2-phenyl-cyclopropanecarboxamide or apharmaceutically acceptable salts thereof.
10. The compound according to claim 1, wherein the compound is
49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl-ethyl}-amide or a pharmaceutically acceptable salts thereof.
11. A method of treating a subject suffering from a disease or disorder comprising administering a therapeutically effective amount of a compound of claim 1, wherein the disease or disorder is selected from the group consisting of psychosis, schizophrenia, cognitive disorders, cognitive impairment associated with schizophrenia, attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, Alzheimer’s disease (AD), mild cognitive impairment (MCI), age associated memory impairment (AAMI), senile dementia, AIDS dementia, Pick’s disease, dementia associated with Lewy bodies, dementia associated with Down’s syndrome, Huntington’s disease, Parkinson’s disease (PD), obsessive-compulsive disorder (OCD), traumatic brain injury, epilepsy, post-traumatic stress, Wernicke-Korsakoff syndrome (WKS), post-traumatic amnesia, and cognitive deficits associated with an underlying condition, wherein the underlying condition is depression, diabetes, weight control, inflammatory disorders, reduced angiogenesis, amyotrophic lateral sclerosis and pain.
12. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
13. A kit comprising a compound of claim 1 and a second compound selected from the group consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
14. The compound according to claim 1 having a diastereomeric excess of at least 85%.
15. The compound according to claim 1 having a diastereomeric excess of at least 90%.
16. The compound according to claim 1 having a diastereomeric excess of at least 95%.