ABSTRACT
Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.
Subject(s)
Antiviral Agents , Azetidines , Oxindoles , Respiratory Syncytial Virus Infections , Spiro Compounds , Humans , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/drug therapy , Animals , Oxindoles/chemistry , Oxindoles/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/pharmacokinetics , Spiro Compounds/administration & dosage , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/administration & dosage , Azetidines/chemistry , Azetidines/pharmacology , Azetidines/administration & dosage , Azetidines/pharmacokinetics , Pre-Exposure Prophylaxis/methods , Injections, Intramuscular , Indoles/chemistry , Indoles/administration & dosage , Indoles/pharmacology , Injections, Subcutaneous , Respiratory Syncytial Virus, Human/drug effects , Virus Internalization/drug effectsABSTRACT
Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds (Ra)-10 and (Ra)-15, possessing remarkable cellular potency and properties.
ABSTRACT
Nitriles are recurring motifs in bioactive molecules and versatile functional groups in synthetic chemistry. Despite recent progress, direct introduction of a nitrile moiety in heteroarenes remains challenging. Recent developments in electrochemical reactions pave the way to more practical cyanation protocols. However, currently available methods typically require hazardous cyanide sources, expensive mediators, and often suffer from narrow substrate scope and laborious reaction set-up. To address the limitations of current synthetic methods, herein, an effective, sustainable, and scalable procedure for the direct C(sp2 )-H cyanation of aromatic N-heterocycles with a user-friendly flow-electrochemical set-up is reported. Furthermore, high substrate and functional-group tolerance is demonstrated, allowing late-stage functionalization of drug-like scaffolds, such as natural products and pharmaceuticals.
Subject(s)
Biological Products , Nitriles , CyanidesABSTRACT
Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure-activity relationship (SAR) trends observed.
Subject(s)
Antiviral Agents/chemistry , Drug Discovery/methods , Imidazolidines/chemistry , Indoles/chemistry , Respiratory Syncytial Virus, Human/drug effects , Viral Fusion Protein Inhibitors/chemistry , Administration, Oral , Antiviral Agents/administration & dosage , Crystallography, X-Ray/methods , HeLa Cells , Humans , Imidazolidines/administration & dosage , Indoles/administration & dosage , Protein Structure, Secondary , Respiratory Syncytial Virus, Human/physiology , Viral Fusion Protein Inhibitors/administration & dosageABSTRACT
Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.
Subject(s)
Antiviral Agents/chemistry , Hepatitis B virus/drug effects , Pyrimidines/chemistry , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Computer Simulation , Cytokines/biosynthesis , Dogs , Hepatitis B/drug therapy , Hepatitis B/virology , Hepatitis B virus/physiology , High-Throughput Screening Assays , Humans , Macaca fascicularis , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
The enantioselective synthesis of the title compound, using Meyers' bicyclic lactam methodology, is described. This compound and a few of its derivatives are useful intermediates in natural product synthesis.
Subject(s)
Indenes/chemical synthesis , Ketones/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Indenes/chemistry , Ketones/chemistry , Lactams/chemistry , StereoisomerismABSTRACT
The synthesis and biological activity of novel CD-ring modified analogues of 22-oxa-1alpha,25-dihydroxyvitamin D(3), lacking the D-ring and featuring a connection between C-12 and C-21 (cis-perhydrindane CE-ring analogues), is described. The synthesis of the CE-ring system follows Meyers' methodology for the preparation of enantiomerically pure hydrinden-2-ones. The analogues show a complete lack of binding affinity for the vitamin D receptor (pig nVDR) and of antiproliferative activity (MCF-7 cells), as compared to calcitriol.