ABSTRACT
Although treatment of multiple myeloma (MM) with daratumumab significantly extends the patient's lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study.
Subject(s)
Antibodies, Bispecific , Multiple Myeloma , Animals , Mice , ADP-ribosyl Cyclase 1/metabolism , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/therapeutic use , Multiple Myeloma/drug therapy , T-Lymphocytes/pathologyABSTRACT
Heavy chain (Hc) heterodimers represent a majority of bispecific antibodies (bsAbs) under clinical development. Although recent technologies achieve high levels of Hc heterodimerization (HD), traces of homodimer contaminants are often present, and as a consequence robust purification techniques for generating highly pure heterodimers in a single step are needed. Here, we describe two different purification methods that exploit differences in Protein A (PA) or Protein G (PG) avidity between homo- and heterodimers. Differential elution between species was enabled by removing PA or PG binding in one of the Hcs of the bsAb. The PA method allowed the avidity purification of heterodimers based on the VH3 subclass, which naturally binds PA and interferes with separation, by using a combination of IgG3 Fc and a single amino acid change in VH3, N82aS. The PG method relied on a combination of three mutations that completely disrupts PG binding, M428G/N434A in IgG1 Fc and K213V in IgG1 CH1. Both methods achieved a high level of heterodimer purity as single-step techniques without Hc HD (93-98%). Since PA and PG have overlapping binding sites with the neonatal Fc receptor (FcRn), we investigated the effects of our engineering both in vitro and in vivo. Mild to moderate differences in FcRn binding and Fc thermal stability were observed, but these did not significantly change the serum half-lives of engineered control antibodies and heterodimers. The methods are conceptually compatible with various Hc HD platforms such as BEAT® (Bispecific Engagement by Antibodies based on the T cell receptor), in which the PA method has already been successfully implemented.
Subject(s)
Antibodies, Bispecific , Antibodies, Monoclonal , Bacterial Proteins/chemistry , Immunoglobulin Fc Fragments , Staphylococcal Protein A/chemistry , Antibodies, Bispecific/chemistry , Antibodies, Bispecific/immunology , Antibodies, Bispecific/isolation & purification , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , HEK293 Cells , Humans , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin Fc Fragments/immunology , Immunoglobulin Fc Fragments/isolation & purificationABSTRACT
Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure-activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC50s: <15â¯nM) along with adequate metabolic stability. Lead compounds 30 and 58 exhibited good exposure and oral bioavailability in mouse pharmacokinetic (PK) study. Compound 30 was selected for further profiling and revealed comparable mouse and rat GSNOR potency, high selectivity against alcohol dehydrogenase (ADH) and carbonyl reductase (CBR1) family of enzymes, low efflux ratio and permeability in PAMPA, a high permeability in CALU-3 assay, significantly low hERG activity and minimal off-target activity. Further, an in vivo efficacy of compound 30 is disclosed in cigarette smoke (CS) induced mouse model for COPD.
Subject(s)
Aldehyde Oxidoreductases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Tetrazoles/chemistry , Tetrazoles/pharmacology , Administration, Oral , Aldehyde Oxidoreductases/metabolism , Animals , Cigarette Smoking/adverse effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Halogenation , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/metabolism , Structure-Activity Relationship , Tetrazoles/administration & dosage , Tetrazoles/pharmacokineticsABSTRACT
In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950â¯nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6â¯mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106â¯mg/kg).
Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Enzyme Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/metabolism , Furans/pharmacology , Imidazoles/pharmacology , Prostaglandin-E Synthases/antagonists & inhibitors , Administration, Oral , Animals , Cell Line, Tumor , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Furans/administration & dosage , Furans/chemistry , Guinea Pigs , Humans , Hyperalgesia/drug therapy , Imidazoles/administration & dosage , Imidazoles/chemistry , Macaca fascicularis , Molecular Structure , Pain/drug therapy , Prostaglandin-E Synthases/metabolism , Rats , Structure-Activity RelationshipABSTRACT
This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50â¯nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3â¯mg/kg in guinea pig.
Subject(s)
Enzyme Inhibitors/chemistry , Furans/chemistry , Imidazoles/chemistry , Prostaglandin-E Synthases/antagonists & inhibitors , A549 Cells , Administration, Oral , Animals , Dogs , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Guinea Pigs , Half-Life , Humans , Hyperalgesia/drug therapy , Imidazoles/pharmacokinetics , Imidazoles/therapeutic use , Inhibitory Concentration 50 , Macaca fascicularis , Microsomes, Liver/metabolism , Prostaglandin-E Synthases/metabolism , Rats , Solubility , Structure-Activity RelationshipABSTRACT
A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F=33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model.
Subject(s)
Imidazoles/chemistry , Prostaglandin-E Synthases/antagonists & inhibitors , A549 Cells , Administration, Oral , Animals , Cyclooxygenase 1/chemistry , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Dinoprostone/metabolism , Disease Models, Animal , Guinea Pigs , Half-Life , Humans , Hyperalgesia/drug therapy , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Imidazoles/therapeutic use , Inhibitory Concentration 50 , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Prostaglandin-E Synthases/genetics , Prostaglandin-E Synthases/metabolism , Rats , Structure-Activity RelationshipABSTRACT
The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo. Compound 17d {2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide} exhibited excellent mPGES-1 enzyme (IC50: 8nM), cell (A549 IC50: 16.24nM) and human whole blood potency (IC50: 249.9nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED50 of 36.7mg/kg, respectively.
Subject(s)
Benzimidazoles/pharmacology , Dioxanes/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Hyperalgesia/drug therapy , Pain/drug therapy , Prostaglandin-E Synthases/antagonists & inhibitors , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Dioxanes/chemical synthesis , Dioxanes/chemistry , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Guinea Pigs , Hot Temperature , Humans , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Mice , Molecular Structure , Prostaglandin-E Synthases/metabolism , Rats , Structure-Activity RelationshipABSTRACT
We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (Cmax = 44 ng/mL; AUC0-t = 359 ng · h/mL) at 10 mg/kg was due to the formation of O-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC-MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug 25b, which upon oral dosing resulted in an improved pharmacokinetic profile (Cmax = 359 ng.h/mL; AUC0-t = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug 25b showed good efficacy in selected rodent models of psychosis.
Subject(s)
Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/drug effects , Pyridones/chemical synthesis , Pyridones/pharmacology , Acetates/chemical synthesis , Acetates/pharmacokinetics , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Area Under Curve , Dogs , Drug Design , Female , Glucuronides/metabolism , Macaca fascicularis , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Phosphodiesterase Inhibitors/pharmacokinetics , Prodrugs , Psychoses, Substance-Induced/drug therapy , Pyridones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimization of this primary series resulted in the identification of 1-methyl-3-(4-{[3-(pyridine-4-yl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-b]pyridine 13a with good hPDE10A potency (IC50: 6.3 nM), excellent selectivity over other related PDEs and desirable physicochemical properties. The compound exhibited high peripheral and adequate brain levels upon oral dosing in rodents. The compound also showed excellent efficacy in multiple preclinical animal models related to psychiatric disorders, particularly schizophrenia.
Subject(s)
Drug Design , Ethers/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Pyrazines/pharmacology , Pyridines/pharmacology , Animals , Dogs , Dose-Response Relationship, Drug , Ethers/administration & dosage , Ethers/chemistry , Haplorhini , Humans , Male , Mice , Molecular Structure , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/chemistry , Pyrazines/administration & dosage , Pyrazines/chemistry , Pyridines/administration & dosage , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We report analogue-based rational design and synthesis of two novel series of polycyclic heteroarenes, pyrrolo[3,2-b]quinolines and pyrido[2,3-b]indoles, tethered to a biaryl system by a methyl-, ethyl- or propyl ether as PDE10A inhibitors. A number of analogues were prepared with variable chain length and evaluated for their ability to block PDE10A enzyme using a radiometric assay. Detailed SAR analyses revealed that compounds with an ethyl ether linker are superior in potency compared to compounds with methyl or propyl ether linkers. These compounds, in general, showed poor metabolic stability in rat and human liver microsomes. The metabolic profile of one of the potent compounds was studied in detail to identify metabolic liabilities of these compounds. Structural modifications were carried out that resulted in improved metabolic stability without significant loss of potency.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Quinolines/chemistry , Quinolines/pharmacology , Animals , Drug Design , Humans , Indoles/chemical synthesis , Indoles/metabolism , Microsomes, Liver/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/metabolism , Quinolines/chemical synthesis , Quinolines/metabolism , Rats , Structure-Activity RelationshipABSTRACT
The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.
Subject(s)
Imidazoles/chemistry , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/chemistry , Thiazoles/chemistry , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Disease Models, Animal , Dizocilpine Maleate/toxicity , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Female , Half-Life , Molecular Docking Simulation , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/metabolism , Psychotic Disorders/drug therapy , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/therapeutic useABSTRACT
A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9nM) showed a good pharmacokinetic profile upon oral dosing at 10mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain.
Subject(s)
Amides/chemistry , Analgesics/chemical synthesis , Piperidines/chemistry , Spiro Compounds/chemistry , TRPM Cation Channels/antagonists & inhibitors , Administration, Oral , Amides/pharmacokinetics , Amides/therapeutic use , Analgesics/pharmacokinetics , Analgesics/therapeutic use , Animals , Disease Models, Animal , Half-Life , Male , Mice , Mice, Inbred C57BL , Neuralgia/drug therapy , Protein Binding , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , TRPM Cation Channels/metabolismABSTRACT
BACKGROUND: Liquid chromatography-tandem mass spectrometry (LC/MS/MS)-based in vitro cytochrome P450 (CYP) inhibition assays in pooled human liver microsomes using therapeutically relevant probe drugs are recommended by the US Food and Drug Administration to assess the potential for drug-drug interactions. As these assays are used routinely in pharmaceutical drug discovery screening of new chemical entities for drug interaction liabilities, there is a need to have higher analytical throughput. Column-switching methods may offer increased chromatographic throughput while maintaining the quality of data generated. METHODS: In this study, the CYP3A4 inhibition assay was used as a potential application to demonstrate the performance of a dual-column parallel chromatographic system in a column-switching mode. Testosterone 6ß-hydroxylation was monitored and IC50 values of known CYP3A4 inhibitors were determined using conventional as well as column-switching LC/MS/MS methods. RESULTS: Mean IC50 values of ketoconazole, itraconazole and verapamil were 0.056, 0.061 and 23 µM (conventional method) compared to 0.05, 0.057 and 26 µM (column-switching method), respectively. The two different chromatographic methods resulted in IC50 values that were not statistically different and were within a twofold range, demonstrating reproducibility of results. Further, the column-switching method saved nearly 50% of analytical time in comparison to the conventional chromatographic method, indicating increased throughput leading to better utilization of mass spectrometer time without compromising the quality of data. CONCLUSIONS: Similar column-switching methods may be used for other isoforms as well and offer a convenient increased analytical throughput in CYP inhibition assays.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/pharmacology , Microsomes, Liver/enzymology , Steroid Hydroxylases/pharmacology , Chromatography, Liquid/methods , Humans , Inhibitory Concentration 50 , Mass Spectrometry , Tandem Mass Spectrometry/methodsABSTRACT
The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Parkinson Disease/drug therapy , Pyridones/pharmacology , Animals , Cyclic Nucleotide Phosphodiesterases, Type 7/metabolism , Dose-Response Relationship, Drug , Drug Stability , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Imidazoles/chemistry , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Parkinson Disease/enzymology , Parkinson Disease/metabolism , Pyridones/chemistry , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationship studies of isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors are discussed. The pharmacokinetic profile of 10 and 21 with adequate CNS penetration, required for in vivo Parkinson's disease models, are disclosed.