A5041183323- Pharmacogenetics and Drug Metabolism
- Receptor Mechanisms and Signaling
- Protein Kinase Regulation and GTPase Signaling
- Treatment of Major Depression
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Pancreatic function and diabetes
- Cannabis and Cannabinoid Research
- Tryptophan and brain disorders
- Inflammatory mediators and NSAID effects
- Biotin and Related Studies
- Cardiac electrophysiology and arrhythmias
- Drug Transport and Resistance Mechanisms
- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Cancer Genomics and Diagnostics
- Pain Mechanisms and Treatments
- Advanced biosensing and bioanalysis techniques
- Stress Responses and Cortisol
- Computational Drug Discovery Methods
- CRISPR and Genetic Engineering
- Nicotinic Acetylcholine Receptors Study
- Alkaline Phosphatase Research Studies
- MicroRNA in disease regulation
- Alcohol Consumption and Health Effects
Bristol-Myers Squibb (United States)
2013-2024
Biocon (India)
2013-2022
Bristol-Myers Squibb (India)
2013-2022
Syngene International (India)
2013-2020
Bristol-Myers Squibb (Germany)
2017
Biocon (Switzerland)
2017
Mount Sinai Medical Center
2008
Inflammation Research Foundation
2005-2008
University of Illinois Chicago
2002
Baylor College of Medicine
2002
Rapsyn, a peripheral membrane protein of skeletal muscle, clusters nicotinic acetylcholine receptors (nAChRs) at high density in the postsynaptic membrane. The mechanism nAChR clustering by rapsyn was analyzed expressing nAChRs HEK293T cells with various fragments mouse fused to green fluorescent protein. Membrane targeting is conferred solely its acylated N terminus, as myristoylated N-terminal 15 amino acids are sufficient target plasma However, neither myristoylation nor conserved acid...
Rapsyn, a 43-kDa peripheral membrane protein of skeletal muscle, is essential for clustering nicotinic acetylcholine receptors (nAChR) in the postsynaptic membrane. Previous studies with rapsyn NH(2)-terminal fragments fused to green fluorescent protein, expressed 293T cells along nAChRs, establish following: Rapsyn-(1-90), containing myristoylated amino terminus and two tetratricopeptide repeats (TPRs), was sufficient self-association at plasma membrane; rapsyn-(1-287), seven TPRs, did not...
Rapsyn, a peripheral membrane protein of skeletal muscle, is necessary for the formation highly organized structure vertebrate neuromuscular junction. For mice lacking rapsyn, there failure postsynaptic specialization characterized by an absence nicotinic acetylcholine receptors (nAChRs) and other integral proteins such as β-dystroglycan utrophin. Dystroglycan mature junction has been shown to interact directly with rapsyn. Previous studies rapsyn fragments mutants, expressed in 293T cells...
The optimization of a class indole cPLA 2 alpha inhibitors is described herein. importance the substituent at C3 and substitution pattern phenylmethane sulfonamide region are highlighted. Optimization these regions led to discovery 111 (efipladib) 121 (WAY-196025), which shown be potent, selective in variety isolated enzyme assays, cell based rat human whole blood assays. binding compounds has been further examined using isothermal titration calorimetry. Finally, have efficacy when dosed...
The synthesis and structure-activity relationship of a series indole inhibitors cytosolic phospholipase A2alpha (cPLA2alpha, type IVA phospholipase) are described. Inhibitors cPLA2alpha predicted to be efficacious in treating asthma as well the signs symptoms osteoarthritis, rheumatoid arthritis, pain. introduction benzyl sulfonamide substituent at C2 was found impart improved potency these inhibitors, SAR analogues is disclosed. Compound 123 (Ecopladib) sub-micromolar inhibitor GLU micelle...
Recent literature reports highlight the importance of renal outer medullary potassium (ROMK) channel in sodium and homeostasis emphasize potential impact that ROMK inhibitors could have as a novel mechanism diuretic heart failure patients. A series piperazine-based were designed optimized to achieve excellent potency, hERG selectivity, ADME properties, which led identification compound
We previously cloned Siva-1 by using the cytoplasmic tail of CD27, a member tumor necrosis factor receptor family, as bait in yeast two-hybrid system. The Siva gene is organized into four exons that code for predominant full-length transcript, whereas its alternate splice form, Siva-2, lacks exon 2 coding sequence. Various groups have demonstrated role several apoptotic pathways. Interestingly, proapoptotic properties are lacking Siva-2. fact partly localized to mitochondria despite absence...
Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been and show efficacy in various rodent pain models. (S)-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was highly selective, CNS penetrant, potent inhibitor from novel class bi(hetero)aryl ethers. BMS-986176/LX9211 showed excellent two models central...
Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (4), highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced into phase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be selective inhibitors with good druglike properties. Among these, 43 58 showed very efficacy...
Expression and functional changes in the organic anion transporting polypeptide (OATP)-multidrug resistance-associated protein (MRP) axis of transporters are well reported patients with nonalcoholic steatohepatitis (NASH). These can impact plasma tissue disposition endo- exogenous compounds. The transporter alterations often assessed by administration a xenobiotic or proteomic analysis from liver biopsies. Using gene expression, proteomics, endogenous biomarkers, we show that expression...
(<i>R</i>)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3<i>S</i>,4<i>S</i>)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen (BMS-986163) were identified from a drug discovery effort focused on development of novel, intravenous glutamate <i>N</i>-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD)....
There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein discovery preclinical profile water-soluble intravenous prodrug BMS-986163 (6) its active parent molecule BMS-986169 (5), which high binding affinity site (Ki = 4.0 nM) selective inhibition function (IC50 24 in cells. The...
Galectin-3 (Gal-3), a β-galactoside-binding lectin, has been implicated in plethora of pathological disorders including fibrosis, inflammation, cancer and metabolic diseases. TD139-a thio-digalactoside inhibitor developed by Galecto Biotech as potential therapeutic for idiopathic pulmonary fibrosis-is the most advanced small-molecule Gal-3 clinical studies. It binds to human with high affinity but lower towards mouse rat homologs, which is also manifested differential inhibition function....
Summary Background Existing treatments for asthma are not effective in all patients and disease exacerbations common, highlighting the need increased understanding of mechanisms novel treatment strategies. The leukotriene pathway including enzyme responsible arachidonic acid release from cellular phospholipids, cPLA 2 α, is a major contributor to asthmatic responses an attractive target therapies. Objective study reported here investigates (a) differential effects vitro exposure peripheral...
Background and Purpose Activators of K v 11.1 (hERG) channels have potential utility in the treatment acquired congenital long QT (LQT) syndrome. Here, we describe a new hERG channel activator, 5‐(((1H–indazol‐5‐yl)oxy)methyl)‐N‐(4‐(trifluoromethoxy)phenyl)pyrimidin‐2‐amine (ITP‐2), with chemical structure distinct from previously reported compounds. Experimental Approach Conventional electrophysiological methods were used to assess effects ITP‐2 on hERG1a hERG1a/1b expressed heterologously...
Fatty acid amide hydrolase (FAAH) is a membrane-associated enzyme that catalyzes the hydrolysis of several endogenous bioactive lipids, including anandamide (AEA), N-palmitoylethanolamine (PEA), oleamide, and N-oleoylethanolamine (OEA). These fatty amides participate in many physiological activities such as analgesia, anxiety, sleep modulation, anti inflammatory responses, appetite suppression. Because FAAH plays an essential role controlling tone activity these this has been implicated to...
Cynomolgus monkeys are a commonly used species in preclinical drug discovery, and have high genetic similarity to humans, especially for the drug-metabolizing cytochrome P450s. However, differences frequently observed metabolism of drugs between cynomolgus delineating these requires expressed CYPs. Toward this end, monkey CYP3A4 (c3A4) was cloned novel human embryonic kidney 293-6E cell suspension system. Following preparation microsomes, kinetic profiles five known (h3A4) substrates...
The carboxyl-terminal 28 amino acids of rabbit cytochrome P450 2C2 are markedly different from those other 2C family members and, substitution the equivalent P450s can confer novel steroid hydroxylase activity to while normal lauric acid is retained. To determine basis for activity, 2C1 were substituted and mutants expressed in COS-1 cells. There 13 differences between sequences this region, including five nonconservative exchanges charged uncharged acids. However, only valine Ser-473...
A hybrid cytochrome P450, C2MstC1, with 306 N-terminal amino acids derived from P450 2C2 sequence and 184 C-terminal 2C1 acquires a novel progesterone 21-hydroxylase activity which is absent in the parent enzymes. Extension of to residue 382 reduced hydroxylase 5% that while further extension 411 or 462 increased back about 30 40%, respectively. In chimera 382, substitution at positions 368, 369, 374 level equivalent C2MstC1. extending 411, substitutions 386 388, addition those 374, were...