A5029340600- HIV/AIDS drug development and treatment
- Hepatitis C virus research
- Oxidative Organic Chemistry Reactions
- Asymmetric Synthesis and Catalysis
- HIV Research and Treatment
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Catalytic C–H Functionalization Methods
- Biochemical and Molecular Research
- Bioactive Compounds and Antitumor Agents
- Radiopharmaceutical Chemistry and Applications
- Computational Drug Discovery Methods
- Chemical synthesis and alkaloids
- Protein Degradation and Inhibitors
- Pharmacogenetics and Drug Metabolism
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Fluorine in Organic Chemistry
- Prostate Cancer Treatment and Research
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Alkaloids: synthesis and pharmacology
- Pneumocystis jirovecii pneumonia detection and treatment
- Radical Photochemical Reactions
- Biotechnology and Related Fields
Melinta Therapeutics (United States)
2023
Bristol-Myers Squibb (United States)
2012-2022
Achillion Pharmaceuticals (United States)
2018
HR Wallingford
2017
Scripps Research Institute
2008-2010
Pennsylvania State University
2002-2006
This report details the invention of a method to enable syntheses psychotrimine (1) and kapakahines F B (2, 3) on gram scale in minimum number steps. Mechanistic inquiries are presented for key enabling quaternization indole at C3 position by electrophilic attack an activated aniline species. Excellent chemo-, regio-, diastereoselectivities observed reactions with o-iodoaniline, cation equivalent. Additionally, scope this reaction is broad respect tryptamine components. The anti-cancer...
While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer death is one of the drug discovery challenges facing biomedical research era precision oncology. Attempts to eradicate cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals been successful clinic, but they are limited by number targets given inability intracellular proteins. More recently,...
The putative reductive activation chemistry of the diazoparaquinone antibiotics was modeled with Bu3Sn−H and prekinamycin dimethyl ether along itself. Reaction in various combinations aromatic solvents, without nucleophile benzylmercaptan present, led to isolation both radical-trapping arene adducts nucleophilic capture benzyl thioether products. On basis these product distribution studies, intermediacies of, first, a cyclopentenyl radical and, next, an orthoquinonemethide electrophile are...
Abstract The p53 tumor suppressor protein is the most frequently mutated gene in human cancers. Despite decades of effort, this transcription factor considered a historically “undruggable” target. Mutations DNA binding domain (DBD) result either inability to bind and exert its function, or conformational instability leading aggregation mutant protein. Y220C missense mutation encodes structural that occurs approximately 1% cancers, 20,000 US patients, annually. In recent years, small molecule...
TPS5115 Background: New therapies are urgently needed to treat prostate cancer, especially for patients progressing on existing drugs that inhibit the activity of Androgen Receptor (AR) (e.g. Pathway Inhibitors (ARPIs)). Metastatic Castration-Resistant Prostate Cancer (mCRPC) is a more aggressive stage disease, characterized by increased AR expression and signaling. To address this unmet medical need, we have developed Regulated Induced Proximity Targeting Chimera (RIPTAC™) Therapeutic...
The syntheses of a bis indole and an salicylate with the required axial chirality for diazonamide A are reported. Atropselectivity in these biaryl systems is enforced by sp3 stereogenic center lactone tether both cases.
Iterative structure-activity analyses in a class of highly functionalized furo[2,3-b]pyridines led to the identification second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (14), potential clinical candidate. The key challenge poor metabolic stability was overcome by strategic incorporation deuterium at soft spots. preclinical profile and status (14) is described.
184 Background: Resistance to Androgen Receptor Signaling Inhibitors (ARSIs) in prostate cancer occurs almost all patients and is driven primarily by genomic alterations AR increases expression. In the metastatic castration-resistant setting, more than 80% of these harbor amplifications gene or upstream enhancer region DNA. Our RIPTAC technology leverages high level expression selectively kill cells while sparing normal tissues. Methods: We describe here a novel orally bioavailable...
Treatment of the representative diazoparaquinone prekinamycin dimethyl ether with Bu3SnH/AIBN in aromatic solvents furnishes moderate-to-good yields formal aryl adducts wherein a molecule solvent is attached to carbon (C(11)) previously bearing diazo function. Substituent studies provide evidence support radical substitution mechanism, which addition function generates an intermediate C(11) vinylic radical.
Allosteric HIV-1 integrase inhibitors (ALLINIs) have been of interest recently because their novel mechanism action. Strategic modifications to the C5 moiety a class 4-(4,4-dimethylpiperidinyl)-2,6-dimethylpyridinyl ALLINIs led identification tetrahydroisoquinoline heterocycle as suitable spacer element project distal hydrophobic aryl ring. Subsequent optimization substitutions identified 12 an ALLINI with single-digit nanomolar inhibitory potency and low clearance across preclinical...
The development of a series novel 7-azabenzofurans exhibiting pan-genotype inhibition HCV NS5B polymerase via binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, human serum shift, and metabolic stability were encountered overcome through SAR studies. This work culminated in selection BMS-986139 (43) as preclinical candidate.
1. Due to its unique C-C and C-H bonding properties, conformational preferences relative hydrophilicity, the cyclopropyl ring has been used as a synthetic building block in drug discovery modulate potency drug-like properties. During an effort discover inhibitors of hepatitis C virus non-structural protein 5B with improved genotype-coverage profiles, use pyrimidinylcyclopropylbenzamide moiety linked C6-substituted benzofuran or azabenzofuran core scaffold was explored balance antiviral...
During a medicinal chemistry campaign to identify inhibitors of the hepatitis C virus nonstructural protein 5B (RNA-dependent RNA polymerase), bicyclo[1.1.1]pentane was introduced into chemical scaffold improve metabolic stability. The bearing this feature, 5-(3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-4-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (1) and...
Abstract Background: Novel drugs are needed to tackle forms of prostate cancer that demonstrate resistance hormonal agents. Halda has invented an innovative treatment approach does not rely on oncogenic drivers. Regulated Induced Proximity Targeting Chimera (RIPTAC™) therapeutics heterobifunctional small molecules work via a hold and kill mechanism the potential overcome drug mechanisms. RIPTAC function by holding together two proteins, cancer-specific protein, protein with essential (EP) in...
Allosteric integrase inhibitors (ALLINIs) of HIV-1 may hold promise as a novel mechanism for HIV therapeutics and cure. Core modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class ALLINIs provided series potent compounds with differentiated 5/6 fused ring systems. Notably, containing 1,2,4 triazolopyridine imidazopyridine core exhibited single digit nM antiviral potency low moderate clearance after intravenous (IV) dosing in rat pharmacokinetic (PK) studies. The...
Abstract Review: 8 refs.