Yang W.,Discovery Chemistry |
Wang Y.,Discovery Chemistry |
Lai A.,Discovery Chemistry |
Qiao J.X.,Discovery Chemistry |
And 13 more authors.
Journal of Medicinal Chemistry | Year: 2014
Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y12 and P2Y1. Blocking P2Y12 receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y1 antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y12 inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y1 antagonist, 1. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y 12 antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y1 antagonism as a promising new antiplatelet target. © 2014 American Chemical Society.
PubMed | Discovery Biology, Pharmaceutical Candidate Optimization and Research Parkway
Type: Journal Article | Journal: Drug discovery today. Technologies | Year: 2014
Drug discovery and development faces a growing challenge to improve the success rate of drug candidates and to accelerate the lengthy, expensive process of bringing new medicines to patients. The emerging methodology of biomarker models has the potential to assist in exploring and finding novel drug targets and to aid at an early stage by assessing efficacy, and addressing issues with metabolism, toxicity and pharmacokinetics. Biomarker discovery and monitoring assays depend on sophisticated analytical techniques such as mass spectrometry that provides the sensitivity and specificity required to establish the models.:
Yin Y.,Medicinal Chemistry |
Yin Y.,Shanghai Institute of Technology |
Lin L.,Scripps Research Institute |
Ruiz C.,Scripps Research Institute |
And 10 more authors.
Journal of Medicinal Chemistry | Year: 2013
RhoA and its downstream effector ROCK mediate stress fiber formation and cell contraction through their effects on the phosphorylation of myosin light chain (MLC). Inhibition of the RhoA/ROCK pathway has proven to be a promising strategy for several indications such as cardiovascular disease, glaucoma, and inflammatory disease. In 2010, our group reported urea-based ROCK inhibitors as potential antiglaucoma agents. These compounds showed potent IC50 values in enzymatic and cell-based assays and significant intraocular pressure (IOP)-lowering effects in rats (∼7 mmHg).(22) To develop more advanced ROCK inhibitors targeting various potential applications (such as myocardial infarction, erectile dysfunction, multiple sclerosis, etc.) in addition to glaucoma, a thorough SAR for this urea-based scaffold was studied. The detailed optimization process, counter-screening, and in vitro and in vivo DMPK studies are discussed. Potent and selective ROCK inhibitors with various in vivo pharmacokinetic properties were discovered. © 2013 American Chemical Society.
Davies N.L.,Discovery Biology |
Compson J.E.,Discovery Biology |
MacKenzie B.,Discovery Biology |
O'Dowd V.L.,Discovery Biology |
And 20 more authors.
Clinical and Vaccine Immunology | Year: 2013
Clostridium difficile infections are a major cause of antibiotic-associated diarrhea in hospital and care facility patients. In spite of the availability of effective antibiotic treatments, C. difficile infection (CDI) is still a major cause of patient suffering, death, and substantial health care costs. Clostridium difficile exerts its major pathological effects through the actions of two protein exotoxins, TcdA and TcdB, which bind to and disrupt gut tissue. Antibiotics target the infecting bacteria but not the exotoxins. Administering neutralizing antibodies against TcdA and TcdB to patients receiving antibiotic treatment might modulate the effects of the exotoxins directly. We have developed a mixture of three humanized IgG1 monoclonal antibodies (MAbs) which neutralize TcdA and TcdB to address three clinical needs: reduction of the severity and duration of diarrhea, reduction of death rates, and reduction of the rate of recurrence. The UCB MAb mixture showed higher potency in a variety of in vitro binding and neutralization assays (̃10-fold improvements), higher levels of protection in a hamster model of CDI (82% versus 18% at 28 days), and higher valencies of toxin binding (12 versus 2 for TcdA and 3 versus 2 for TcdB) than other agents in clinical development. Comparisons of the MAb properties also offered some insight into the potential relative importance of TcdA and TcdB in the disease process. Copyright © 2013, American Society for Microbiology. All Rights Reserved.
Zhao P.,Boston Childrens Hospital |
Zhao P.,Harvard University |
Zhao P.,Methodist Hospital Research Institute |
Hou L.,Boston Childrens Hospital |
And 7 more authors.
Journal of Leukocyte Biology | Year: 2014
SerpinB1 is an endogenous inhibitor of serine proteases recognized for its anti-inflammatory and host-protective properties. Although loss of serpinB1 in mice does not result in gross immune deregulation, serpinb1a-/- mice display increased mortality and inflammation-associated morbidity upon challenge with influenza virus. Here, we show that IL-17A+ γδ and CD4+ Th17 cells are already expanded in the lungs of serpinb1a-/- mice at steady-state. Both γδ and αβ+ CD4+ CCR6+ T cells isolated from the lungs of naive serpinb1a-/- mice displayed a skewed transcriptional profile relative to WT cells, including increased Th17 signature transcripts [Il17a, l17f, and Rorc (RORγt)] and decreased Th1 signature transcripts [Ifng, Cxcr3, and Tbx21 (T-bet)] in γδ T cells. In addition to the lung, IL-17A+ γδ and CD4+ Th17 cells were increased in the spleen of naive serpinb1a-/- mice, despite normal αβ and γδ T cell development in the thymus. Within the γδ T cell compartment, loss of serpinb1a prompted selective expansion of Vγ4+ and Vγ6/Vδ1+ cells, which also displayed elevated expression of the proliferating cell nuclear antigen, Ki-67, and IL-17A. Given that serpinb1a is preferentially expressed in WT IL-17A+ γδ and CD4+ Th17 cell subsets vis-à-vis other T cell lineages, our findings reveal a novel function of serpinB1 in limiting untoward expansion of lymphocytes with a Th17 phenotype. © Society for Leukocyte Biology.
Yin Y.,Medicinal Chemistry |
Yin Y.,Shanghai Institute of Technology |
Zheng K.,Medicinal Chemistry |
Eid N.,Discovery Biology |
And 18 more authors.
Journal of Medicinal Chemistry | Year: 2015
The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (>400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors. © 2015 American Chemical Society.
Ogawa S.,Inflammation Research Unit |
Ogawa S.,Pfizer |
Ochi T.,Discovery Biology |
Shimada H.,Inflammation Research Unit |
And 9 more authors.
Hepatology Research | Year: 2010
Aim: To evaluate the usefulness of a platelet-derived growth factor (PDGF)-B specific monoclonal antibody (mAb) as a therapeutic agent to treat chronic liver fibrosis.Methods: Liver fibrosis was induced in ICR mice by bile duct ligation (BDL) or BALB/c mice by weekly injection of concanavalin A (ConA) for 4 or 8-weeks. A mAb specific for mouse and human PDGF-B chain, AbyD3263, was generated, tested in vitro and administered twice a week throughout the experimental period.Results: AbyD3263 showed neutralizing activity against mouse and human PDGF-B chain in cell-based assays, as measured in vitro by inhibition of phosphorylation of PDGF receptor Β and proliferation of hepatic stellate cells induced by PDGF-BB. The half life of AbyD3263 in mice exceeded 7-days and dosing of animals twice a week resulted in constant plasma levels of the mAb. Induction of liver fibrosis by BDL and ConA resulted in elevated levels of alanine aminotransferase (ALT) in plasma and hydroxyproline in the liver. Treatment with AbyD3263 did not modify ALT levels, but significantly reduced hydroxyproline content in the liver with a maximum reduction of 39% and 54% in the BDL and ConA models, respectively, compared to controls.Conclusios: Consistent with the notion that PDGF-BB plays an important role in the progression of liver fibrosis, AbyD3263 exhibits efficacy in pre-clinical disease models suggesting that pharmacological inhibition of PDGF-B chain may be a therapeutic approach to treat liver fibrosis. © 2010 The Japan Society of Hepatology.
News Article | December 8, 2016
FREMONT, Calif.--(BUSINESS WIRE)--While NOACs are increasingly replacing warfarin to treat thromboembolism – blood clots – they have an increased risk of bleeding and bleeding complications, which can be life-threatening1. Preclinical research presented at the ASH (American Society of Hematology) Annual Meeting on Monday demonstrated that multiple novel anticoagulants from Verseon are as effective as the NOACs at preventing thrombosis, but with a much-reduced bleeding risk. The research presented by Verseon’s Dr Mohan Sivaraja, Associate Director of Discovery Biology, showed that Verseon’s new class of direct thrombin inhibitors (VE-DTIs) are able to preserve platelet function while still blocking fibrinogen cleavage, a primary event in blood clot formation2. Platelet function plays an important role in wound healing, healthy tissue growth, and hemostasis (stopping of bleeding). The observed preservation of platelet function indicates a reason why the VE-DTIs have a significantly reduced bleeding risk when compared to current NOACs. The presentation detailed a number of in vivo tests, including the arteriovenous shunt and thrombin-induced thromboembolism models, which demonstrate that the VE-DTIs effectively prevent thrombosis while preserving platelet function. This is further reinforced by in vitro research in which both animal and human blood was put through a number of assays, which confirm that Verseon’s compounds leave platelet function almost unaffected. NOACs, currently the most commonly used anticoagulants, are associated with a high bleeding risk and are known to strongly inhibit thrombin-mediated platelet activation, which affects platelet function3. Verseon’s drug candidates are up to 900-fold less potent in the in vitro inhibition of platelet activation when compared to the NOACs, while they effectively block fibrinogen cleavage. “This unique feature of our novel class of thrombin inhibitors provides a biological explanation for their low bleeding liability,” said Dr. Mohan Sivaraja. “These encouraging results further establish the distinctive pharmacology of our compounds and could lead to improved blood thinners.” Verseon’s new class of anticoagulants has been developed using its proprietary, computationally driven drug discovery platform. This platform can generate better drugs through the design of novel chemical matter. In addition to its anticoagulant program, Verseon currently also has programs on diabetic macular edema and oncology in preclinical testing, all with multiple novel drug candidates. 1 “Risk of Fatal Bleeding in Episodes of Major Bleeding with New Oral Anticoagulants and Vitamin K Antagonists: A Systematic Review and Meta-Analysis” http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137444 2 “Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms” http://www.bloodjournal.org/content/100/3/743?sso-checked=true
Malkapuram S.,Sai Life science Ltd. Pune |
Taran S.,Sai Life science Ltd. Pune |
Venkataraman K.,Vellore Institute of Technology |
Rajagopalan L.,Discovery Biology
International Journal of Pharma and Bio Sciences | Year: 2016
Green Coffee Extract (GCE) is a popular health supplement known for its anti-obesity & anti-diabetic effects. Here we tested GCE for its capacity to activate J774.1 mouse macrophages and protect against Doxorubicin induced apoptosis. J774.1 cells treated for 24 h with 100 and 500 μg/ml GCE showed increased production of IL-6, TNF-α and nitric oxide (NO) in a dose dependent manner. GCE upregulated production of these molecules by inducing transcription of the IL-6, TNF-α and iNOS genes. In addition, GCE was able to restore viability of J774.1 cells treated with Doxorubicin. Pre-treatment of cells with GCE for 1 h abrogated Dox induced loss of cell viability. While Dox robustly induced caspase 3/7 activity within 6 h of treatment, pretreatment with GCE for 1 h was enough to attenuate this induction. The results we report here suggest that GCE activates J774.1 macrophages and is cytoprotective against Dox induced apoptosis.
Malkapuram S.,Sai Life science Ltd |
Venkataraman K.,Vellore Institute of Technology |
Tongaonkar R.,Sai Life science Ltd |
Taran S.,Sai Life science Ltd |
And 2 more authors.
Research Journal of Medicinal Plant | Year: 2016
Green Coffee Extract (GCE), an extract of Coffea arabica bean is a popular health supplement employed for anti-obesity and anti-diabetic effects. Here a hydroalcoholic extract of Green Coffee (GCE) was evaluated for its potential as a cardioprotective agent against Doxorubicin (Dox) induced cardiac insult in a H9C2 rat cardiomyocyte in vitro model system. The GCE was tested in an MTT viability assay using 1 μM Dox with and without GCE pretreatment at 50, 100 and 250 μg mL-1 concentrations. GCE was also tested for its free radical scavenging ability in a DPPH assay at 10 concentrations (500 μg mL-1 maximum concentration). To understand the mechanism of action of cardioprotection, mitochondrial membrane potential (Δψm) was compared between Dox treated cells with and without GCE pretreatment, using the JC-1 dye. Finally, the activation of caspase-3/7 was quantitated. Findings from the above experiments demonstrated that GCE rescued H9C2 cardiomyocytes from Dox induced loss of cell viability in a dose-dependent manner. While Dox treatment caused a clear decrease in the JC-1 ratio from 2 to 1.6 due to loss of Δψm, pre- treatment with GCE at 25, 50 and 100 μg mL-1 restored the JC-1 ratio to 1.6, 1.9 and 2.0, respectively. Dox treatment potently induced caspase 3/7 activity by 5 fold and pre-treatment with GCE at 100 and 500 μg mL-1 reduced this activation to 3.5 and 1.5 fold, respectively. This data clearly demonstrates that GCE is strongly cardioprotective against Dox induced cardiac insult and the mechanism of action is by blocking activation of intrinsic apoptotic pathway. © 2016 Academic Journals Inc.