A5012619985- HIV/AIDS drug development and treatment
- Peptidase Inhibition and Analysis
- HIV Research and Treatment
- HER2/EGFR in Cancer Research
- Click Chemistry and Applications
- Neuropeptides and Animal Physiology
- Chemical Synthesis and Analysis
- Cancer-related Molecular Pathways
- Hepatitis C virus research
- Microtubule and mitosis dynamics
- Synthesis and biological activity
- Cancer therapeutics and mechanisms
- Diabetes Treatment and Management
- Influenza Virus Research Studies
- Protease and Inhibitor Mechanisms
- Quinazolinone synthesis and applications
- Carbohydrate Chemistry and Synthesis
- Monoclonal and Polyclonal Antibodies Research
- Cancer Mechanisms and Therapy
- Cytokine Signaling Pathways and Interactions
- Cancer Treatment and Pharmacology
- Polyamine Metabolism and Applications
- Biochemical and Molecular Research
- Ubiquitin and proteasome pathways
- Cancer, Hypoxia, and Metabolism
High Point University
2022-2023
AbbVie (United States)
2013-2018
Abbott (United States)
2001-2013
Discovery Laboratories (United States)
2013
Abbott Fund
2003-2012
Beatson West of Scotland Cancer Centre
2009-2012
Vatterott College
2011
Pennington Biomedical Research Center
2007
Pennsylvania State University
2007
University Medical Center New Orleans
2007
ABSTRACT The valine at position 82 (Val 82) in the active site of human immunodeficiency virus (HIV) protease mutates response to therapy with inhibitor ritonavir. By using X-ray crystal structure complex HIV and ritonavir, potent ABT-378, which has a diminished interaction Val 82, was designed. ABT-378 potently inhibited wild-type mutant ( K i = 1.3 3.6 pM), blocked replication laboratory clinical strains type 1 (50% effective concentration [EC 50 ], 0.006 0.017 μM), maintained high potency...
In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve an efficient hinge-binding template inhibitors. By incorporating N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, series RTK were generated, which potently inhibited activity vascular endothelial growth factor platelet-derived families. A number compounds with oral...
ABT-378, a new human immunodeficiency virus type 1 (HIV-1) protease inhibitor which is significantly more active than ritonavir in cell culture, currently under investigation for the treatment of AIDS. Development viral resistance to ABT-378 vitro was studied by serial passage HIV-1 (pNL4-3) MT-4 cells. Selection variants with increasing concentrations revealed sequential appearance mutations gene: I84V-L10F-M46I-T91S-V32I-I47V. Further selection at 3.0 microM concentration resulted an...
BILN 2061 is a novel, specific hepatitis C virus (HCV) NS3 serine protease inhibitor discovered by Boehringer Ingelheim that has shown potent activity against HCV replicons in tissue culture and currently under clinical investigation for the treatment of infection. The poor fidelity RNA-dependent RNA polymerase will likely lead to development drug-resistant viruses treated patients. resistance was studied vitro passage genotype 1b replicon cells presence fixed concentration drug. Three weeks...
Novel transient receptor potential vanilloid 1 (TRPV1) antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity blocking capsaicin activation of TRPV1 was assessed. On the basis contribution these to potency, they ranked order 5-isoquinoline > 8-quinoline = 8-quinazoline 8-isoquinoline or cinnoline approximately phthalazine quinoxaline 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 4 nM) exhibited 46% oral...
A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation structure-activity relationships at the 5- and 6-positions thienopyrimidine nucleus led to a N,N'-diaryl ureas that potently inhibit all vascular endothelial growth factor (VEGF) platelet-derived (PDGF) kinases. insert domain-containing (KDR) homology model suggests these compounds bind "inactive conformation" enzyme with urea portion extending into back hydrophobic pocket adjacent...
Compounds A-782759 (an N-1-aza-4-hydroxyquinolone benzothiadiazine) and BILN-2061 are specific anti-hepatitis C virus (HCV) agents that inhibit the RNA-dependent RNA polymerase NS3 serine protease, respectively. Both compounds display potent activity against HCV replicons in tissue culture. In order to characterize development of resistance these anti-HCV agents, subgenomic 1b-N replicon cells were cultured with alone or combination at concentrations 10 times above their corresponding 50%...
PLK1 (polo-like kinase 1) is a key mitotic and therapeutic target in the treatment of proliferative diseases. Here we investigate relative substrate specificity pharmacological relatedness PLK1, -2, -3, -4 that together comprise conserved family Ser/Thr kinases (PLK family). We report consensus sequences for PLK2, an expanded sequence which use to design optimal peptide substrate, PLKtide. inhibitory activity entire PLK across diverse set small-molecule ATP-competitive inhibitors including...
The discovery of (+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N'-ethyl-N'-isopropylcarbamyl)pyrrolidine-4-carboxylic acid (A-192558, 20e) as a potent inhibitor influenza neuraminidase (NA) is described. Efficient syntheses two core structures, cis-3-(allyloxycarbonyl)amino-1-(9'-fluorenylmethoxycarbonyl)pyrrolidine-4-carboxylic (7) and tert-butyl (+/-)-(2S,3R,4R)-2-aminomethyl-3-bis(tert-butyloxycarbonyl)amino-1-(N'-ethyl-N'-isopropylcarbamyl)pyrrolidine-4-carboxylate (18b), were...
Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of Ki = 58 μM via potency enhancement >70 000-fold analogue 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling combinatorial chemistry. Protein crystal structures revealed that inconsistent structure−activity relationship (SAR) data resulted from different binding orientations the inhibitor core...
Abstract The three‐dimensional structure of a secreted aspartic protease from Candida albicans complexed with potent inhibitor reveals variations on the classical theme that dramatically alter specificity this class enzymes. presents: (1) an 8‐residue insertion near first disulfide (Cys 45‐Cys 50, pepsin numbering) results in broad flap extending toward active site; (2) 7‐residue deletion replacing helix h N2 (Ser 110‐Tyr 114), which enlarges S 3 pocket; (3) short polar connection between...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHost-guest complexation. 42. Preorganization strongly enhances the tendancy of hemispherands to form hemispheraplexesKenneth M. Doxsee, Martin Feigel, Kent D. Stewart, Jimmy W. Canary, Carolyn B. Knobler, and Donald J. CramCite this: Am. Chem. Soc. 1987, 109, 10, 3098–3107Publication Date (Print):May 1, 1987Publication History Published online1 May 2002Published inissue 1...
Based on the crystallographic analysis of a urea-checkpoint kinase 1 (Chk1) complex and molecular modeling, class macrocyclic Chk1 inhibitors were designed their biological activities evaluated. An efficient synthetic methodology for ureas was developed with Grubbs metathesis macrocyclization as key step. The structure-activity relationship studies demonstrated that retains full inhibition activity 4-position phenyl ring can tolerate wide variety substituents. These novel exhibit excellent...
Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment type 2 diabetes. They exert their beneficial effects by increasing levels active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which two important incretins glucose homeostasis. Starting from high-throughput screening hit, we were able to identify series piperidinone- piperidine-constrained phenethylamines novel DPP4 inhibitors. Optimized compounds potent,...
Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been found to be overexpressed in variety hematopoietic malignancies solid tumors. Benzothienopyrimidinones were discovered as novel class Pim inhibitors that potently inhibit all three with subnanomolar low single-digit nanomolar Ki values exhibit excellent selectivity against panel diverse kinases. Protein crystal structures the bound Pim-1 complexes benzothienopyrimidinones 3b (PDB code 3JYA), 6e 3JYO), 12b 3JXW)...
ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTCheminformatic Tools for Medicinal ChemistsSteven W. Muchmore, Jeremy J. Edmunds, Kent D. Stewart, and Philip Hajduk*View Author Information Pharmaceutical Discovery Division, Abbott Laboratories, Park, Illinois 60064*To whom correspondence should be addressed. Phone: (847) 937-0368. Fax: 938-2478. E-mail: [email protected]Cite this: Med. Chem. 2010, 53, 13, 4830–4841Publication Date (Web):March 24, 2010Publication History Received5 February...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComplementary solutes enter nonpolar preorganized cavities in lipophilic noncomplementary mediaDonald J. Cram, Kent D. Stewart, Israel Goldberg, and Kenneth N. TruebloodCite this: Am. Chem. Soc. 1985, 107, 8, 2574–2575Publication Date (Print):April 1, 1985Publication History Published online1 May 2002Published inissue 1 April 1985https://pubs.acs.org/doi/10.1021/ja00294a075https://doi.org/10.1021/ja00294a075research-articleACS PublicationsRequest...
A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors a potential treatment diabetes and obesity. X-ray crystallography data show that these bind to the catalytic site DPPIV with cyano group forming covalent bond serine residue DPPIV. The C5-substituents make various interactions enzyme affect potency, chemical stability, selectivity, PK properties inhibitors. Optimized are extremely potent...