A5110621095- Hepatitis C virus research
- Prostate Cancer Treatment and Research
- Asymmetric Synthesis and Catalysis
- Synthetic Organic Chemistry Methods
- Cancer Treatment and Pharmacology
- Protein Degradation and Inhibitors
- HIV/AIDS drug development and treatment
- Chemical Synthesis and Analysis
- Hormonal and reproductive studies
- Microbial Natural Products and Biosynthesis
- Hepatitis B Virus Studies
- Estrogen and related hormone effects
- Peptidase Inhibition and Analysis
- X-ray Diffraction in Crystallography
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- Crystallization and Solubility Studies
- Ubiquitin and proteasome pathways
- Alkaloids: synthesis and pharmacology
- Crystallography and molecular interactions
- Chemical synthesis and alkaloids
- Catalytic Cross-Coupling Reactions
- Coordination Chemistry and Organometallics
- Synthesis of heterocyclic compounds
- Axial and Atropisomeric Chirality Synthesis
Arvinas (United States)
2017-2024
Bristol-Myers Squibb (United States)
2004-2016
Centre Hospitalier Universitaire de Grenoble
2011
Bristol-Myers Squibb (Germany)
2007
Memorial Sloan Kettering Cancer Center
1995-1996
Columbia University
1996
Kettering University
1995
Colorado State University
1991-1994
New Frontier
1994
An intramolecular Heck reaction (90 → 91) serves as the key step in total synthesis of titled compounds. The synthetic route is based on utilizing Wieland−Miescher ketone (5) a matrix to provide C and D rings targets functionality implements for joining this sector an A ring precursor (6). Catalytically induced enantiotopic control early emplacement oxetane are other features route.
259 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during transition from a localized to metastatic disease. Most patients initially respond inhibitors AR pathway, but response is often relatively short-lived. majority progressing on enzalutamide or abiraterone exhibit genetic alterations in locus, either form amplifications point mutations gene. Given these mechanisms resistance, our goal eliminate protein using PROteolysis...
The intramolecular Heck reaction of 1 to 2 is the cornerstone this total synthesis taxol (see conversion below). route starts with (S)-Wieland Miescher ketone, and oxetane ring installed early in synthesis. Elaboration a CD fragment, addition an A nucleophile, further manipulations yield appropriate starting material (1) for reaction. After key step yielding 2, baccatin III (and thence taxol) concludes cleavage exo double bond at C-10 oxygenation C-9 C-13.
ABSTRACT Using a cell-based replicon screen, we identified class of compounds with thiazolidinone core structure as inhibitors hepatitis C virus (HCV) replication. The concentration one such compound, BMS-824, that resulted in 50% inhibition HCV replication was ∼5 nM, therapeutic index >10,000. compound showed good specificity for HCV, it not active against several other RNA and DNA viruses. Replicon cells resistant to BMS-824 were isolated, mutations identified. A combination amino acid...
Abstract ARV-471, an estrogen receptor (ER) alpha PROTAC® protein degrader, is a hetero-bifunctional molecule that facilitates the interactions between and intracellular E3 ligase complex, leading to ubiquitylation subsequent degradation of receptors via proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with half-maximal concentration (DC50) ~ 1 nM. mediated decreases expression classically regulated ER-target genes inhibits proliferation ER-dependent (MCF7,...
Abstract Prostate cancer is the second leading cause of death in men United States. The androgen receptor (AR) plays critical roles both early disease and advanced prostate cancer. Current therapeutic approaches targeting androgen/AR axis are initially effective, but castration resistant (CRPC) inevitably develops. CRPC tightly linked with increased AR activity via gene overexpression, amplification, gain-of-function mutations. To address these mechanisms AR-dependent tumor growth, we have...
The iminothiazolidinone BMS-858 (2) was identified as a specific inhibitor of HCV replication in genotype 1b replicon assay via high-throughput screening campaign. A more potent analogue, BMS-824 (18), used resistance mapping studies, which revealed that inhibitory activity related to disrupting the function nonstructural protein 5A. Despite development coherent and interpretable SAR, it subsequently discovered DMSO 18 underwent an oxidation structural rearrangement afford thiohydantoin 47,...
The biphenyl derivatives 2 and 3 are prototypes of a novel class NS5A replication complex inhibitors that demonstrate high inhibitory potency toward panel clinically relevant HCV strains encompassing genotypes 1–6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. structure–activity relationship investigations improved the properties parent bis-phenylimidazole chemotype, culminating identification highly potent inhibitor daclatasvir...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe synthesis of aracemic 4-substituted pyrrolidinones and 3-substituted pyrrolidines. An asymmetric (-)-rolipramA. I. Meyers Lawrence SnyderCite this: J. Org. Chem. 1993, 58, 1, 36–42Publication Date (Print):January 1993Publication History Published online1 May 2002Published inissue 1 January 1993https://doi.org/10.1021/jo00053a012RIGHTS & PERMISSIONSArticle Views1031Altmetric-Citations92LEARN ABOUT THESE METRICSArticle Views are the...
Abstract The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during transition from a localized to metastatic disease. Most patients initially respond inhibitors AR pathway, but response is often short-lived. majority progressing on enzalutamide or abiraterone exhibit genetic alterations in locus, either form amplifications point mutations gene. Given these mechanisms resistance, our goal eliminate protein using PROteolysis TArgeting Chimera...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA practical, enantioselective synthesis of SK&F 104353Joseph R. Flisak, Kerry J. Gombatz, Monica M. Holmes, Alvydas A. Jarmas, Ivan Lantos, Wilford L. Mendelson, Vance Novack, James Remich, and Lawrence SnyderCite this: Org. Chem. 1993, 58, 23, 6247–6254Publication Date (Print):November 1, 1993Publication History Published online1 May 2002Published inissue 1 November...
Hepatitis C virus (HCV) non-structural protein 5A (NS5A) is a multi-functional that expressed in basally phosphorylated (p56) and hyperphosphorylated (p58) forms. NS5A phosphorylation has been implicated regulating multiple aspects of HCV replication. We recently reported the identification class compounds potently inhibit RNA replication by targeting NS5A. Although precise mechanism inhibition these not well understood, one activity described their ability to block expression form Here, we...
ABSTRACT The exceptional in vitro potency of the hepatitis C virus (HCV) NS5A inhibitor BMS-790052 has translated into an vivo effect proof-of-concept clinical trials. Although 50% effective concentration (EC 50 ) initial lead, thiazolidinone BMS-824, was ∼10 nM replicon assay, it underwent transformation to other inhibitory species after incubation cell culture medium. biological profile including EC , drug required reduce growth by (CC ), and resistance profile, however, remained...
<div>Abstract<p>Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone enzalutamide) are standard treatments for metastatic hormone-sensitive cancer castration-resistant cancer. However, continual evolution during progression can result in <i>AR</i> alterations mutation, amplification, splicing) cause tumors to become resistant these therapies. Bavdegalutamide (ARV-110) a PROteolysis TArgeting...
<p>Supplementary Figure S2 shows the effect of bavdegalutamide on neomorphic substrates</p>
<p>Supplementary Figure S3 shows the effect of bavdegalutamide on SALL4</p>
<p>Supplementary Figure S4 shows maintenance of animal body weights during treatment with bavdegalutamide or enzalutamide in prostate cancer mouse models</p>
<p>Supplementary Figure S1 shows the effect of bavdegalutamide on AR versus AR-V7</p>
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAsymmetric conjugate additions to chiral bicyclic lactams. Synthesis of aracemic trans-2,3-disubstituted pyrrolidinesA. I. Meyers and Lawrence SnyderCite this: J. Org. Chem. 1992, 57, 14, 3814–3819Publication Date (Print):July 1, 1992Publication History Published online1 May 2002Published inissue 1 July 1992https://pubs.acs.org/doi/10.1021/jo00040a018https://doi.org/10.1021/jo00040a018research-articleACS PublicationsRequest reuse permissionsArticle...
A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and 1b (G-1b) replicon inhibition selectivity against BVDV cytotoxicity. SAR emerging an examination prolinamide cap region revealed 11 be a selective NS5A inhibitor exhibiting submicromolar potency both G-1a G-1b replicons. Additional structural refinements resulted in identification 30 as potent, dual G-1a/1b inhibitor.
By targeting the flap backbone of BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved inhibitory activity over lead compound 1. The cocrystal structure bound to site indicated two hydrogen-bond interactions between dimethylisoxazole and threonine 72 glutamine 73 flap. Incorporation substitution onto related carboxamide series led pyrazine-carboxamide 26 as a very potent inhibitor (IC50 < 1 nM). This demonstrated robust brain Aβ...