A5085149487- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- CAR-T cell therapy research
- HIV/AIDS drug development and treatment
- Ubiquitin and proteasome pathways
- Hepatitis C virus research
- Quinazolinone synthesis and applications
- Mast cells and histamine
- Cancer-related gene regulation
- Chromatin Remodeling and Cancer
- Estrogen and related hormone effects
- Receptor Mechanisms and Signaling
- Synthesis and Catalytic Reactions
- Histone Deacetylase Inhibitors Research
- Click Chemistry and Applications
- Monoclonal and Polyclonal Antibodies Research
- Hepatitis B Virus Studies
- Biochemical and Molecular Research
- Phagocytosis and Immune Regulation
- Synthesis and biological activity
- Asthma and respiratory diseases
- Hormonal Regulation and Hypertension
- Olfactory and Sensory Function Studies
- Synthesis and Reactions of Organic Compounds
- Synthesis and Reactivity of Heterocycles
Victoria University of Wellington
2023
AbbVie (United States)
2013-2020
Abbott Fund
1993-2009
Abbott (United States)
2003-2009
University of Leeds
2008
Sarepta Therapeutics (United States)
2005
Discovery Laboratories (United States)
2004
Ligand Pharmaceuticals (United States)
2001-2003
Monsanto (United States)
1992
The development of bromodomain and extraterminal domain (BET) inhibitors their examination in clinical studies, particularly oncology settings, has garnered substantial recent interest. An effort to generate novel BET with excellent potency drug metabolism pharmacokinetics (DMPK) properties was initiated based upon elaboration a simple pyridone core. Efforts develop bidentate interaction critical asparagine residue resulted the incorporation pyrrolopyridone core, which improved by 9–19-fold....
We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to 2R,5R analogues. Furthermore, attachment substituents 4-position central N-phenyl group resulted in compounds potency. Substitution tert-butyl, as compound 38 (ABT-267), low-picomolar EC50 values superior It was discovered that a pan-genotypic...
Abstract ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered phase I clinical trials. Comprehensive preclinical characterization of demonstrated broad activity across cell lines tumor models, representing variety hematologic malignancies solid indications. In most cancer derived from tumors, triggers prominent G1 cell-cycle arrest without extensive apoptosis. this study, we show efficiently apoptosis in acute myeloid leukemia (AML), non-Hodgkin lymphoma,...
The BET family of proteins consists BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 BD2). bromodomain inhibitors under clinical development for oncology bind to each the eight with similar affinities. We hypothesized that it may be possible achieve an improved therapeutic index by selectively targeting subsets bromodomains. Both BD1 BD2 are highly conserved across members (>70% identity), whereas from same exhibit a larger degree divergence (∼40% suggesting...
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%...
Members of the BET family bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety cancer cell lines. A two-dimensional NMR fragment screen binders to bromodomains BRD4 phenylpyridazinone with weak binding affinity (1, Ki = 160 μM). SAR investigation 1, aided by X-ray structure-based design, enabled synthesis potent pyridone and macrocyclic inhibitors exhibiting single digit nanomolar potency both biochemical based assays. Advanced...
The preparation and characterization of a series C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as novel class selective ligands for the glucocorticoid receptor is described. Substitution at position tetracyclic core with linear, two-atom appendages (OCH(3), OCF(2)H, NHMe, SMe, CH=CH(2), Ctbd1;CH, CH(2)OH) provided molecules high affinity (K(i) = 2-8 nM) human (hGR) limited cross-reactivity other steroid receptors (PR, MR, AR, ER). Optimal analogues...
The preparation and characterization of a series selective glucocorticoid receptor modulators are described. preliminary structure-activity relationship nonaromatic C-5 substitution on the tetracyclic quinoline core showed preference for small lipophilic side chains. Proper at this position maintained transcriptional repression proinflammatory transcription factors while diminishing activation activity ligand/glucocorticoid complex. optimal compounds described in study were allyl analogue 18...
Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component these is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the inhibitors, do not exhibit equivalent efficacy against genotypes 1–6. In particular, first inhibitors tend to select viral drug resistance. Ombitasvir inhibitor included as key Viekira Pak treatment with...
Little is known about the mechanism of HCV polymerase-catalyzed nucleotide incorporation and individual steps employed by this enzyme during a catalytic cycle. In paper, we applied various biochemical tools examined polymerase catalysis. We found that formation productive RNA-enzyme complex slowest step followed RNA dissociation initiation primer strand synthesis. Various groups have reported several classes small molecule inhibitors hepatitis C virus NS5B polymerase; however, inhibition for...
In search of a uroselective alpha1A subtype selective antagonist, novel series 6-OMe hexahydrobenz[e]isoindoles attached to bicyclic heterocyclic moiety via two-carbon linker was synthesized. It found that in contrast the previously described tricyclic heterocycles,(1) this has very specific requirements for attachments. The most important structural features contributing alpha1A/alpha1B selectivity these compounds were identified. vitro functional assays alpha1 adrenoceptor subtypes used...
Abstract: A‐331440 {4′‐[3‐(3( R )‐(dimethylamino)‐pyrrolidin‐1‐yl)‐propoxy]‐biphenyl‐4‐carbonitrile}, a potent and selective antagonist of histamine H 3 receptors, yielded positive results in an vitro micronucleus assay, predictive genotoxicity vivo . Because this compound has highly favourable properties potential as antiobesity agent, new compounds general chemical class were sought that would retain or improve upon the high potency selectivity for but lack obtained with compound. Our...
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of program to identify new direct-acting antivirals (DAAs) for the treatment infection. This compound identified during medicinal chemistry effort improve on an original lead, 1, which we described in previous publication. Replacement amide linkage 1 with trans-olefin resulted improved permeability and solubility provided much better pharmacokinetic properties preclinical species. dihydrouracil N-linked...