pathology

PLX5622 is a highly selective brain penetrant and oral active CSF1R inhibitor.

alphaSYN-IN-NAB2, a neuron-protective agent, is a protein encoded by the NAB2 gene. NAB2 effectively and selectively protects a variety of cells from alpha-SYN toxicity. NAB2 promotes endosomal transport dependent on E3 ubiquitin ligase Rsp5/Nedd4. NAB2 identifies a viable molecular node in alpha-SYN biology that corrects multiple aspects of its underlying pathology, including dysfunctional endosomes and endoplasmic reticulum to Golgi vesicles transport. NAB2 is involved in cellular processes such as cell differentiation, apoptosis and stress response, and can be used to study cancer, neurodevelopment and neuronal activity.

Selisistat (EX-527) is a potent and specific inhibitor of the deacetylase SIRT1 (IC50=38 nM). Selisistat can be used in the study of neurological disorders such as Huntington's chorea.

Advanced glycation end products (AGEs) are compounds formed by non-enzymatic chemical reactions following the bonding of sugars to proteins or lipids during diabetes, uremia, aging, rheumatic arthritis, and other conditions. A receptor for the AGEs (RAGE) binds certain members of this class to initiate cell signaling.[1][2] Pentosidine is a well-characterized natural AGE that is often used as a biomarker for the production of all AGEs. While pentosidine can be measured in urine, the majority of this AGE is catabolized before excretion.[3] Reference：[1]. Neeper, M., Schmidt, A.M., Brett, J., et al. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. The Journal of Biological Chemisty 267(21), 14998-15004 (1992).[2]. Brett, J., Schmidt, A.M., Yan, S.D., et al. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. American Journal of Pathology 143(6), 1699-1712 (1993).[3]. Miyata, T., Ueda, Y., Horie, K., et al. Renal catabolism of advanced glycation end products: The fate of pentosidine. Kidney International 53, 416-422 (1998).

Sulfatides are endogenous sulfoglycolipids with various biological activities in the central and peripheral nervous systems, pancreas, and immune system. They are produced from the combination of ceramide and UDP-galactose in the endoplasmic reticulum followed by sulfation in the Golgi apparatus. The ceramide portion contains variable fatty acid chain lengths, which are tissue- and pathology-dependent. Sulfatides are primarily found in the myelin sheath of oligodendrocytes and Schwann cells, with smaller chain lengths predominant during development and longer chain lengths predominant in mature cells. They accumulate in the lysosome of patients with metachromatic leukodystrophy, a disorder characterized by arylsulfatase A deficiency. Sulfatides are also located in pancreatic β-cells and inhibit insulin release from isolated rat pancreatic islet cells, suggesting a potential role in diabetes. Sulfatides can induce inflammation in glia in vitro and certain sulfatides, such as C24:1 3'-sulfo-galactosylceramide, can induce an immune response in vitro in mouse splenocytes. Sulfatides (bovine) (sodium salt) is a mixture of isolated bovine sulfatides.

NLRP3 modulators 1 (WO2017184746A1, compound 107) is a potent modulator of NLRP3, capable of agonizing or partially agonizing the activity of NLRP3. This compound proves valuable in investigating conditions, diseases, or disorders where a reduction in LRP3 activity plays a role in the pathology.

(±)12-HETE is one of the six monohydroxy fatty acids produced by the non-enzymatic oxidation of arachidonic acid. The biological activity of (±)12-HETE is similar to that of its constituent enantiomers . It aggregates neutrophils with an EC50 value of 40 nM.[1] Reference：[1]. O'Flaherty, J.T., Thomas, M.J., Lees, C.J., et al. Neutrophil-aggregating activity of monohydroxyeicosatetraenoic acids. American Journal of Pathology 104, 55-62 (1981).

Type II collagen is composed of a triple helix of three identical α chains. These molecules associate to form a fibril that is stabilized by intermolecular crosslinks1. Damage to the fibrillar meshwork, made up of primarily type II collagen (z 90–95%), ma

PMX-205 is a cyclic hexapeptide that acts as a potent antagonist of C5a receptor (C5aR; IC50= 31 nM).1It is orally active and blocks inflammatory signaling and symptoms in animal models of colitis and allergic asthma.2,3PMX-205 is also brain penetrant and reduces neuroinflammation and neurodegeneration in an animal model of Alzheimer's disease.4 1.March, D.R., Proctor, L.M., Stoermer, M.J., et al.Potent cyclic antagonists of the complement C5a receptor on human polymorphonuclear leukocytes. Relationships between structures and activityMol. Pharmacol.65(4)868-879(2004) 2.Jain, U., Woodruff, T.M., and Stadnyk, A.W.The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10Br. J. Pharmacol.168(2)488-501(2013) 3.Staab, E.B., Sanderson, S.D., Wells, S.M., et al.Treatment with the C5a receptor/CD88 antagonist PMX205 reduces inflammation in a murine model of allergic asthmaInt. Immunopharmacol.21(2)293-300(2014) 4.Fonseca, M.I., Ager, R.R., Chu, S.-H., et al.Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's diseaseJ. Immunol.183(2)1375-1383(2009)

NPT200-11 is an orally bioavailable and brain penetrating inhibitor of accumulation of alpha-synuclein (ASYN) misfolding and aggregation. NPT200-11 can be used in studies about the underlying pathology of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA).

BNC-1 is a modulator of amyloid pathology. BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in well-established mouse models of amyloid deposition by promoting phosphorylation and activation of Elk-1.

D-GsMTx4 TFA, a selective spider venom peptide, is a TRPC1/6 and Piezo2 inhibitor that inhibits cation-permeable mechanosensitive channels (MSCs) belonging to the Piezo and TRP channel families, blocks cation-selective stretch-activated channels (SACs), and attenuates lysophosphatidylcholine (LPC)-induced astrocyte toxicity and microglia reactivity. toxicity and microglia reactivity.D-GsMTx4 TFA prevented myocardial infarction in a mouse model of ischemia/reperfusion and can be used to characterize the role of excitatory MSCs in normal physiology and pathology.

MMP13-IN-5 (compound 13m) is a potent, selective MMP-2/MMP-13 inhibitor with IC50 values of 3.6 μM for MMP-2 and 14.6 μM for MMP-13, implicated in the pathology of osteoarthritis (OA) [1].

MBX-8025 is an agonist of peroxisome proliferator-activated receptor δ (PPARδ).1 It is greater than 750- and 2,500-fold selective for PPARδ over PPARα and PPARγ. MBX-8025 (10 mg/kg per day for eight weeks) reduces increases in fasting blood glucose and serum insulin levels, and decreases insulin resistance in Alms1 mutant (foz/foz) mice fed an atherogenic diet as a model of diet-induced obesity, type 2 diabetes, and non-alcoholic steatohepatitis (NASH).2 It also decreases serum alanine transaminase (ALT), as well as serum and hepatic cholesterol and triglyceride, levels and reduces markers of NASH in the same model. |1. Bays, H.E., Schwartz, S., Littlejohn, T., 3rd, et al. MBX-8025, a novel peroxisome proliferator receptor-δ agonist: Lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J. Clin. Endocrinol. Metab. 96(9), 2889-2897 (2011).|2. Haczeyni, F., Wang, H., Barn, V., et al. The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice. Hepatol. Commun. 1(7), 663-674 (2017).

β-Amyloid (12-28) (TFA), a peptide fragment of the β-amyloid protein (β1-42)—a 42 amino acid protein primarily found in senile plaque cores—exhibits aggregation properties. This compound holds significance for research into Alzheimer’s disease, highlighting its potential utility in understanding the disease's pathology [1].

IL-17A modulator-2, exhibits inhibitory properties towards IL-17A, with a pIC50 of 8.3. Its effectiveness lies in attenuating the biological effects associated with IL-17A activity. IL-17A modulator-2 finds utility in the study of diseases and disorders characterized by dysregulated IL-17A modulation, such as those involving immune dysfunction, autoimmune pathology, cancer, and neurodegenerative conditions.

PD146176 (NSC-168807) is an inhibitor of 15-Lipoxygenase (15-LO) , it inhibits rabbit reticulocyte 15-LO with Ki of 197 nM and IC50 of 0.54 μM. PD146176 reverses cognitive impairment, brain amyloidosis, and tau pathology by stimulating autophagy in aged triple transgenic mice.

MMP13-IN-4 (compound 13) is a potent, selective MMP-13 inhibitor with an IC50 of 14.6 μM, implicated in the pathology of osteoarthritis (OA) [1].

UFP-803 TFA, a potent ligand for the urotensin-II receptor (UT), exhibits minimal residual agonist activity, rendering it a valuable asset for exploring the UT system's function in physiology and pathology [1].

SSTR4 agonist 4 is a potent SSTR4 agonist that has the potential for the pain research. SSTR4 agonists are effective in rodent models of pain associated with acute and chronic associated anti-peripheral nociceptive and anti-inflammatory activity. SSTR4 is expressed at relatively high levels in the hippocampus and neocortex, regions of memory and learning, and in Alzheimer's disease pathology [1].

SSTR4 agonist 3 is a potent compound that activates the SSTR4 receptor. The SSTR4 receptor is highly expressed in the hippocampus and neocortex, which are regions associated with memory, learning, and Alzheimer's disease pathology. SSTR4 agonists demonstrate strong efficacy in rodent models of pain, both acute and chronic, by reducing peripheral nociception and inflammation. Considering its potential application in pain research, SSTR4 agonist 3 is of interest[1].

THK-523 has shown selectivity and high affinity for tau pathology both in vitro and in vivo. 18 F-THK523 is a potent tau imaging radiotracer which is a potent in vivo tau imaging ligand for Alzheimer's disease [1].

Rasagiline-13C3is intended for use as an internal standard for the quantification of rasagiline by GC- or LC-MS. Rasagiline is an inhibitor of monoamine oxidase B (MAO-B; IC50= 4.43 nM for the rat brain enzyme).1It is selective for MAO-B over MAO-A (IC50= 412 nM for the rat brain enzyme). It inhibits serum and NGF withdrawal-induced apoptosis of PC12 cells when used at concentrations ranging from 0.01 to 100 μM.2Rasagiline inhibits rat brain MAO-Bin vivo(ED50= 0.1 mg/kg).1It reduces cerebral edema in a mouse model of traumatic brain injury.2Rasagiline (0.1 mg/kg) reduces cortical and hippocampal levels of full-length and soluble amyloid precursor protein (APP) in rats and mice. It also reduces α-synuclein-induced substantia nigral neuron loss and improves motor dysfunction in a mouse model of Parkinson's disease.3Formulations containing rasagiline have been used in the treatment of Parkinson's disease. 1.Youdim, M.B.H., Gross, A., and Finberg, J.P.Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase BBrit. J. Pharmacol.132(2)500-506(2001) 2.Youdim, M.B.H., and Weinstock, M.Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R) aminoindan-5-YL)-ethyl methyl carbamate]Cell. Mol. Neurobiol.21(6)555-573(2001) 3.Kang, S.S., Ahn, E.H., Zhang, Z., et al.α-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson's diseaseEMBO J.37(12)e98878(2018)

BF 126 has potential applications in vivo imaging of tau pathology in Alzheimer's disease

IDT is an orally active TNFα modulator. It acts by altering neutrophil infiltration, improving cognition and diminishing tau and amyloid pathology in the 3xTgAD mouse model.

Pyrithiamine is the pyridine analog of thiamine that prevents growth of organisms that require intact thiamine. [1] It inhibits the growth of bacterial and fungal species at a pyrithiamine:thiamine ratio of 10:1 in growth media and induces symptoms of thiamine deficiency in mice at a dietary ratio of 3:1. These effects are reversible with addition of sufficient thiamine in all species. Pyrithiamine inhibits the formation of cocarboxylase from thiamine in chicken blood in a dose-dependent manner. [2] It has been used to induce thiamine deficiency in various disease models, including rat models of alcoholism and diencephalic amnesia, to study the effects of thiamine deficiency on disease pathology.[3] [4] Reference：[1]. Woolley, D.W., and White, A.G.C. Selective reversible inhibition of microbial growth with pyrithiamine. J. Exp. Med. 78(6), 489-497 (1943).[2]. Woolley, D.W. An enzymatic study of the mode of action of pyrithiamine (neopyrithiamine). J. Biol. Chem. 191(1), 43-54 (1951).[3]. Vetreno, R.P., Anzalone, S.J., and Savage, L.M. Impaired, spared, and enhanced ACh efflux across the hippocampus and striatum in diencephalic amnesia is dependent on task demands. Neurobiol. Learn Mem. 90(1), 237-244 (2008).[4]. Zahr, N.M., Sullivan, E.V., Rohlfing, T., et al. Concomitants of alcoholism: Differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo. Psychopharmacology (Berl) 233(14), 2675-2686 (2016).

SR1555 is a selective RORγ inverse agonist that inhibits the development and function of TH17 cells, a subset of T cells that have been involved in the pathology of several autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

Q134R, a neuroprotective derivative of hydroxyquinoline, effectively inhibits nuclear factor of activated T-cell (NFAT) signaling and possesses the ability to cross the blood-brain barrier. This compound shows promise for research into Alzheimer’s disease (AD) and aging-related disorders[1].

PLX5622 hemifumarate is a highly selective brain penetrant and orally active CSF1R inhibitor with an IC 50 of 0.016 μM and Ki of 5.9 nM. PLX5622 hemifumarate allows for extended and specific microglial elimination, preceding and during pathology development. In vivo, PLX5622 hemifumarate demonstrates desirable PK properties in varies animals [1] [2].

(S)-Rasagiline mesylate is rasagiline S-isomer, and is an agent of anti-Parkinson.

Rasagiline (AGN1135) is an inhibitor of monamine oxidase used as adjunctive therapy in combination with levodopa and carbidopa in the management of Parkinsons disease.

(S)-Rasagiline is rasagiline S-isomer, and is an agent of anti-Parkinson.

Racemic rasagiline, also known as AGN-1135, is a Monoamine Oxidase type-B inhibitor (MAOI). However, application of this drug can lead to fatal hypertensive crisis in patients who consume tyramine-rich foods. TVP-1022 is the (S)-isomer os Rasagiline and acts as a cardioprotective agent.

Rasagiline 13C3 mesylate racemic is the deuterium labeled Rasagiline, which is an irreversible monoamine oxidase inhibitor.

Rasagiline Mesylate (AGN1135) is a novel MAO-B inhibitor, which can treat idiopathic Parkinson's disease.