A5040034830- Blood Coagulation and Thrombosis Mechanisms
- Hemophilia Treatment and Research
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- DNA and Nucleic Acid Chemistry
- RNA and protein synthesis mechanisms
- Antiplatelet Therapy and Cardiovascular Diseases
- Venous Thromboembolism Diagnosis and Management
- Carbohydrate Chemistry and Synthesis
- Advanced biosensing and bioanalysis techniques
- Protein Degradation and Inhibitors
- Hepatitis C virus research
- Ubiquitin and proteasome pathways
- Hepatitis B Virus Studies
- Chemical Synthesis and Analysis
- Prostate Cancer Treatment and Research
- Platelet Disorders and Treatments
- Cyclopropane Reaction Mechanisms
- Histone Deacetylase Inhibitors Research
- Catalytic C–H Functionalization Methods
- Peptidase Inhibition and Analysis
- Synthesis and Characterization of Heterocyclic Compounds
- Click Chemistry and Applications
- Bacteriophages and microbial interactions
- Chromatin Remodeling and Cancer
- Innovative Microfluidic and Catalytic Techniques Innovation
Bristol-Myers Squibb (United States)
2013-2024
SK Life Science (United States)
2024
Bristol-Myers Squibb (Germany)
2002-2015
Experimental Station
2002
Wilmington University
2000
DuPont (United States)
2000
Scripps Research Institute
1997-1999
Texas A&M University
1991
The structure and activity of the pseudodisaccharide core found in aminoglycoside antibiotics was probed with a series synthetic analogues which position amino groups varied around glucopyranose ring. naturally occurring neamine best according to assays for vitro RNA binding antibiotic activity. With this result hand, used as common synthesis new antibiotics, were evaluated models Escherichia coli 16S A-site ribosomal RNA, protein inhibition, Analysis revealed some correlation between...
The specificity of neomycin B and related aminoglycoside antibiotics in their interaction with the Rev responsive element (RRE) HIV-1 mRNA has been studied by directly observing aminoglycoside−RNA complexes using surface plasmon resonance. Several different RNA sequences, each a biotin tag, have prepared T7 polymerase-catalyzed transcription synthetic DNA templates immobilized on streptavidin-coated for binding study. results indicate that is not specific G-rich bubble region RRE. Rather, it...
Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs compromised by unwanted sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need an antiplatelet with strong efficacy low risk. Thrombin potent platelet agonist directly induces activation via G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 PAR4. A...
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
Particularly stable complexes with bidentate binding are formed between 1,3-hydroxyamines and dimethylphosphate, which serve as models of the by aminoglycoside antibiotics such neomycin B (1) RNA phosphodiesters. This recognition motif involving a hydrogen bond hydroxyl group is also found in complexation anions simple aminoglycosides aqueous solution.
Incorporation of a methyl group onto macrocyclic FVIIa inhibitor improves potency 10-fold but is accompanied by atropisomerism due to restricted bond rotation in the structure, as demonstrated NMR studies. We designed conformational constraint favoring desired atropisomer which this interacts with S2 pocket FVIIa. A incorporating was prepared and reside predominantly conformation. This modification improved 180-fold relative unsubstituted, racemic macrocycle selectivity. An X-ray crystal...
Protease-activated receptor 4 (PAR4) is a G-protein coupled that expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays key role in blood coagulation, its importance pathological thrombosis has been increasingly recognized recent years. Herein, we describe optimization of series imidazothiadiazole antagonists to first-in-class clinical candidate, BMS-986120 (43), backup BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy minimal...
Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment ER-positive (ER+) breast cancers, but new strategies are urgently needed to overcome clinical resistance. In present study, we describe discovery and extensive evaluation ERD-12310A as exceptionally potent orally efficacious PROTAC degrader ERα. achieved a DC
On the basis of a crystal structure phenylpyrrolidine lead and subsequent molecular modeling results, we designed synthesized novel series macrocyclic FVIIa inhibitors. The optimal 16-membered macrocycle was 60-fold more potent than an acyclic analog. Further potency optimization by incorporation P1' alkyl sulfone P2 methyl groups provided with TF/FVIIa Ki = 1.6 nM, excellent selectivity against panel seven serine proteases, FVII-deficient prothrombin time EC2x 1.2 μM. Discovery this potent,...
PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort discover novel antagonist chemotype, quinoxaline-based HTS hit 3 low μM potency was identified. Optimization the through use positional SAR scanning and design conformationally constrained cores led discovery quinoxaline-benzothiazole series as potent selective antagonists. The lead compound 48, possessing 2 nM IC50 against activation...
Despite the development of highly effective therapies for treatment estrogen receptor α (ERα)-positive human breast cancer, clinical resistance to current requires novel therapeutic strategies. Herein, we report discovery ERD-1233 as a potent and orally efficacious ERα degrader designed using PROTAC technology. was developed based on Lasofoxifene ER binding moiety cereblon ligand through extensive optimization linker. potently effectively reduces protein in vitro achieves excellent oral...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDesign of an N7-Glycosylated Purine Nucleoside for Recognition GC Base Pairs by Triple Helix FormationJuerg Hunziker, E. Scott Priestley, Helmut Brunar, and Peter B. DervanCite this: J. Am. Chem. Soc. 1995, 117, 9, 2661–2662Publication Date (Print):March 1, 1995Publication History Published online1 May 2002Published inissue 1 March 1995https://pubs.acs.org/doi/10.1021/ja00114a036https://doi.org/10.1021/ja00114a036research-articleACS...
Factor (F) VIIa in association with tissue factor (TF) is the primary vivo initiator of blood coagulation and activates FX FIX to generate thrombin, which plays a key role pathogenesis thrombosis. We evaluated enzyme kinetics, antithrombotic antihaemostatic properties BMS-593214, an active-site, direct FVIIa inhibitor. Studies were conducted enzymatic assays, anesthetised rabbit models electrically-induced carotid arterial thrombosis (AT), thread-induced vena cava venous (VT) cuticle...
A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical NMR assays is described. This led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among novel inhibitory fragments identified were aryl halides, lactams, heterocycles. Crystallographic structures bound obtained, leading successful design a potent inhibitor...
The previously unreported alpha,alpha-disubstituted 1-aminoboronate esters have potential utility in peptidomimetic design, particularly against serine protease targets. A concise synthesis of 1-aminocyclopropaneboronate pinanediol ester is reported, and a peptidyl derivative shown to modest affinity (K(i) = 1.6 microM) for hepatitis C NS3 protease.
Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On basis a zwitterionic phenylglycine acylsulfonamide 1, benzylamide 2 was shown to possess improved permeability oral bioavailability. Optimization benzylamide, guided by X-ray crystallography, led potent TF-FVIIa inhibitor 18i with bioavailability, but promiscuous activity an vitro safety panel receptors enzymes....
Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization P' groups led to a series highly potent selective TF-FVIIa inhibitors displayed poor permeability. Fluorination reduced basicity P1 group significantly improved The resulting lead compound was potent, selective, achieved good...
Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy preclinical thrombosis models with minimal bleeding liabilities. Discovery potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes required highly basic group S1 binding pocket for high affinity. A recently reported fragment screening effort resulted discovery neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds...
In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in monkey thrombosis model. Beginning with high-throughput screening hit, identified imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure–activity relationship studies enabled optimization potent, selective, orally bioavailable antagonist, UDM-001651. UDM-001651 was evaluated model shown robust...