A5006858899- Chemokine receptors and signaling
- Cytokine Signaling Pathways and Interactions
- Psoriasis: Treatment and Pathogenesis
- Immune Cell Function and Interaction
- IL-33, ST2, and ILC Pathways
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Asthma and respiratory diseases
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Biosimilars and Bioanalytical Methods
- Liver Disease Diagnosis and Treatment
- Protein purification and stability
- Inflammatory mediators and NSAID effects
- Crystallography and molecular interactions
- Synthesis and biological activity
- Gut microbiota and health
- Diabetes and associated disorders
- Quinazolinone synthesis and applications
- Dermatology and Skin Diseases
- Synthesis and Reactions of Organic Compounds
- Drug Transport and Resistance Mechanisms
- Advanced Proteomics Techniques and Applications
- Mass Spectrometry Techniques and Applications
- Fibroblast Growth Factor Research
Bristol-Myers Squibb (United States)
2014-2023
Intestinal IgA, which is regulated by gut microbiota, has a crucial role in maintenance of intestinal homeostasis and protecting the intestines from inflammation. However, means microbiota promotes IgA responses remain unclear. Emerging evidence suggests that host can sense bacterial metabolites addition to pathogen-associated molecular patterns recognition these small molecules influences immune response beyond. We reported here metabolite short-chain fatty acid acetate promoted responses,...
Deucravacitinib, a novel, oral, selective inhibitor of tyrosine kinase 2 (TYK2) signaling, acts via an allosteric mechanism by binding to the enzyme's regulatory domain instead catalytic domain. This unique provides high functional selectivity for TYK2 versus closely related Janus kinases (JAKs) 1/2/3. Deucravacitinib was efficacious in phase and 3 psoriasis trials, without clinical or laboratory parameters indicative JAK 1/2/3 inhibition being observed. analysis compared specificities...
(1) Background: With new potential drug targets emerging, combination therapies appear attractive to treat non-alcoholic steatohepatitis (NASH) and fibrosis. Chemokine receptor CCR2/5 antagonists can improve fibrosis by reducing monocyte infiltration altering hepatic macrophage subsets. Fibroblast growth factor 21 (FGF21) may NASH modulating lipid glucose metabolism. We compared effects of single treatment as therapeutic strategies against NASH. (2) Methods: analyzed serum samples liver...
The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 CCR5 were induced in PDAC following treatment with anti-PD-1 antibody (αPD-1); thus, we examined vaccine or radiation therapy (RT) as T cell priming mechanisms together BMS-687681, a dual antagonist (CCR2/5i), combination αPD-1 new strategies. Using mouse models, demonstrated RT followed...
The gut microbiota has been shown critical for mucosal adjuvant activity of cholera toxin (CT), a potent adjuvant. However, the mechanisms involved remain largely unknown. In this study, we report that depletion bacteria significantly decreased and systemic Ab responses in mice orally immunized with OVA CT. Feeding short-chain fatty acids (SCFAs) promoted elicited by CT, and, more importantly, rescued antibiotic-treated mice. addition, deficient GPR43, receptor SCFAs, showed impaired...
Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds potent in an IL-17 human whole blood assay exhibited excellent oral bioavailability mouse pharmacokinetic studies. This led to the identification compound 5, which displayed dose-dependent inhibition IL-17F production a IL-2/IL-23 stimulated pharmacodynamic model. In addition, 5 was studied acanthosis imiquimod-induced models skin inflammation, where it demonstrated...
RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, has been identified potential target for treatment various immunological disorders psoriasis, psoriatic arthritis, inflammatory bowel diseases. Structure computer-assisted drug design led to identification novel series tricyclic inverse agonists with significantly improved in vitro activity reporter (Gal4) human whole blood assays compared our...
BMS-813160 (compound 3) was identified as a potent and selective CCR2/5 dual antagonist. Compound 3 displayed good permeability at pH = 7.4 in PAMPA experiments demonstrated excellent human liver microsome stability. Pharmacokinetic studies established that had oral bioavailability exhibited low clearance dog cyno. also studied the mouse thioglycollate-induced peritonitis model, which confirmed its ability to inhibit migration of inflammatory monocytes macrophages. As result this profile,...
Abstract The role of retinoid-related orphan receptor γ t (RORγt) in Th17 cell differentiation has been well established; however, how it regulates other T lineages is still not clearly understood. In this study, we report that mice, while promoting differentiation, RORγt inhibited IL-10 production by cells, thereby preserving the pathogenicity cells. Treatment with RORγt-specific inhibitor suppressed signature cytokines, but promoted production. inhibitor–treated cells induce less severe...
Aim: IP-10 is a protein target for the treatment of Crohn's disease. Inhibition by anti-IP-10 mAbs neutralizes its various biological activities. The measurement free suppression as engagement biomarker required assessment drug effect on target. Results: development highly sensitive immunoaffinity-LC–MS/MS assays quantifying and total in cynomolgus monkey serum reported first time. This paper details strategies maximizing assay sensitivity selecting digestion routes, optimizing immunocapture...
We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead a new series dual CCR2 CCR5. Installation γ-lactam as spacer group quinazoline benzamide mimetic improved oral bioavailability markedly. These efforts led identification 13d, potent orally bioavailable antagonist suitable for use in both murine monkey models inflammation.
Structure-activity relationship studies directed toward the replacement of fused phenyl ring lead hexahydrobenzoindole RORγt inverse agonist series represented by 1 with heterocyclic moieties led to identification three novel aza analogs 5-7. The hexahydropyrrolo[3,2-f]quinoline 5 (X = N, Y Z=CH) showed potency and metabolic stability comparable but improved in vitro membrane permeability serum free fraction. This structural modification was applied hexahydrocyclopentanaphthalene 3,...
To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure–activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to identification 2d (BMS-753426) as potent and orally bioavailable antagonist CCR2. Compared previous clinical candidate 1a, tert-butyl amine showed significant improvements pharmacokinetic properties, with lower clearance higher oral bioavailability. Furthermore, compound exhibited improved affinity for CCR5...
Abstract CCR2 and CCR5 are two chemokine receptors that important in the pathogenesis of animal models autoimmune diseases. Since play complementary roles immune system, targeting both simultaneously might afford greater efficacy than either alone. The present study describes identification characterization BMS-A, an orally bioavailable small-molecule CCR2/5-dual antagonist. BMS-A was identified as active against radioligand binding assays. Functional assays biochemical studies demonstrate...
Background: Surrogate monoclonal antibodies (mAbs) used in preclinical vivo studies can be challenging to quantify due lack of suitable immunoaffinity reagents or unavailability the mAb protein sequence. Generic were evaluated develop sensitive LC–MS/MS assays. Peptides unknown sequence for selective LC–MS quantification. Results: anti-mouse IgG1 was found an effective reagent, enabling quantification mouse mAbs serum. Selective peptides applied multiplex two rat co-dosed mouse. Conclusion:...