A5055224019- Blood Coagulation and Thrombosis Mechanisms
- HIV/AIDS drug development and treatment
- Catalytic Cross-Coupling Reactions
- HIV Research and Treatment
- Catalytic C–H Functionalization Methods
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Atrial Fibrillation Management and Outcomes
- Antiplatelet Therapy and Cardiovascular Diseases
- Chemical Synthesis and Analysis
- Cyclopropane Reaction Mechanisms
- Adenosine and Purinergic Signaling
- Click Chemistry and Applications
- Vitamin K Research Studies
- Synthesis of β-Lactam Compounds
- Peptidase Inhibition and Analysis
- Venous Thromboembolism Diagnosis and Management
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Biochemical and Molecular Research
- Eicosanoids and Hypertension Pharmacology
- Chemical synthesis and alkaloids
- HIV/AIDS Research and Interventions
- Renin-Angiotensin System Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Protein Structure and Dynamics
Baruch S. Blumberg Institute
2016-2023
Ministry of Defence
2021-2022
Fox Chase Chemical Diversity Center
2021
Bristol-Myers Squibb (United States)
2006-2020
Doylestown Hospital
2016
Bristol-Myers Squibb (Germany)
2002-2014
DuPont (United States)
1996-2008
Wilmington University
1994-2006
Experimental Station
1987-2006
Harvard University
1996-2001
Mechanistic information and structure-based design methods have been used to a series of nonpeptide cyclic ureas that are potent inhibitors human immunodeficiency virus (HIV) protease HIV replication. A fundamental feature these is the urea carbonyl oxygen mimics hydrogen-bonding features key structural water molecule. The success in both displacing mimicking molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized with relatively low molecular weight high...
The discovery of the copper-promoted Chan-Lam coupling reaction with boronic acids more than ten years ago has greatly advanced carbon-heteroatom cross-coupling chemistry. N-arylation/O-arylation methodology is now a powerful new synthetic tool, made even attractive by mild conditions required. Significant progress been in expanding scope and applications as well understanding mechanism this reaction. This review includes an examination various C-X cross-couplings using their derivatives,...
Efforts to identify a suitable follow-on compound razaxaban (compound 4) focused on modification of the carboxamido linker eliminate potential in vivo hydrolysis primary aniline. Cyclization novel bicyclic tetrahydropyrazolopyridinone scaffold retained potent fXa binding activity. Exceptional potency series prompted an investigation neutral P1 moieties that resulted identification p-methoxyphenyl P1, which factor Xa affinity and good oral bioavailability. Further optimization C-3 pyrazole...
Pax3 is a transcription factor whose expression has been used as marker of myogenic precursor cells arising in the lateral somite destined to migrate and populate limb musculature. Accruing evidence indicates that embryologic origins axial appendicular muscles are distinct, muscle abnormalities both mice humans harboring mutations support this distinction. The mechanisms by which affects development unknown. tyrosine kinase receptor for hepatocyte growth factor/scatter encoded c-met...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTCopper-Promoted C−N Bond Cross-Coupling with Hypervalent Aryl Siloxanes and Room-Temperature N-Arylation IodidePatrick Y. S. Lam, Sophie Deudon, Kristin M. Averill, Renhua Li, Ming He, Philip DeShong, Charles G. ClarkView Author Information DuPont Pharmaceuticals Co., Experimental Station P.O. Box 80500, Wilmington, Delaware 19880-0500 Cite this: J. Am. Chem. Soc. 2000, 122, 31, 7600–7601Publication Date (Web):July 20, 2000Publication History...
Modification of a series pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for relative trypsin and plasma kallikrein. Further optimization P(4) moiety led enhanced permeability reduced protein binding. The SAR pharmacokinetic profile this is described herein. These efforts culminated...
Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as point of convergence intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va Ca2+ on phospholipid surface platelets or endothelial cells, factor forms prothrombinase complex, which is responsible for proteolysis prothrombin to catalytically active thrombin. Thrombin, turn, catalyzes cleavage fibrinogen fibrin, thus initiating process that ultimately leads clot formation. Recently, we reported series...
High-resolution X-ray structures of the complexes HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal presence a structural water molecule which is hydrogen bonded to both mobile flaps enzyme and two carbonyls flanking transition-state mimic inhibitors. Using structure−activity relationships C2-symmetric diol inhibitors, computed-aided drug design tools, first principles, we designed synthesized novel class cyclic ureas that incorporates this preorganizes side chain residues into...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNMR and X-ray Evidence That the HIV Protease Catalytic Aspartyl Groups Are Protonated in Complex Formed by a Non-Peptide Cyclic Urea-Based InhibitorToshimasa Yamazaki, Linda K. Nicholson, Paul Wingfield, Stephen J. Stahl, Joshua D. Kaufman, Charles Eyermann, C. Nicholas Hodge, Patrick Y. S. Lam, A. Torchia, Cite this: Am. Chem. Soc. 1994, 116, 23, 10791–10792Publication Date (Print):November 1, 1994Publication History Published online1 May...
Abstract Copper-mediated carbon–heteroatom bond-forming reactions involving a wide range of substrates have been in the spotlight for many organic chemists. This review highlights developments between 2010 and 2019 both stoichiometric catalytic copper-mediated reactions, also examples nickel-mediated under modified Chan–Lam cross-coupling conditions using various nucleophiles; include chemo- regioselective N-arylations or O-arylations. The utilization nucleophiles as coupling partners...
Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents may offer a safety advantage over P2Y12 in terms of reduced liabilities. In this article, we describe the structural modification tert-butyl phenoxy portion lead compound 1 subsequent discovery novel series conformationally constrained ortho-anilino diaryl ureas. particular, spiropiperidine indoline-substituted ureas described potent, orally bioavailable...
Copper(ii)-catalyzed boronic acid promoted chemoselective N-arylation of unprotected aminophenols has been developed. Selective 3-aminophenol is achieved with a Cu(OAc)2/AgOAc combination in MeOH at rt, whereas the N-arylated products 4-aminophenol can be obtained Cu(OAc)2/Cs2CO3 system and benzoic as an additive. These ligand-free conditions "open-flask" chemistry are robust compatible wide range functional groups. The mechanistic investigation for this selective studied by considering...
Factor XIa (FXIa) is a blood coagulation enzyme that involved in the amplification of thrombin generation. Mounting evidence suggests direct inhibition FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using variety approaches to reduce activity, including inhibitors FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On basis this potential, we targeted our efforts at identifying potent with focus on...
In cell cultures, the key residues associated with HIV-1 resistance to cyclic urea-based protease (PR) inhibitors are Val82 and Ile84 of PR. To gain an understanding how these two modulate inhibitor binding, we have measured Ki values three recombinant mutant proteases, I84V, V82F, V82F/I84V, for DMP323 DMP450, determined three-dimensional structures their complexes 2.1−1.9 Å resolution R factors 18.7−19.6%. The mutants increased by 25-, 0.5-, 1000-fold compared wild-type 0.8 0.4 nM...