A5014833368- interferon and immune responses
- Tryptophan and brain disorders
- Drug Transport and Resistance Mechanisms
- X-ray Diffraction in Crystallography
- Cancer Immunotherapy and Biomarkers
- Pharmacological Receptor Mechanisms and Effects
- Oxidative Organic Chemistry Reactions
- Cholesterol and Lipid Metabolism
- Crystallization and Solubility Studies
- Virus-based gene therapy research
- Cholinesterase and Neurodegenerative Diseases
- Catalytic C–H Functionalization Methods
- HIV/AIDS drug development and treatment
- Protease and Inhibitor Mechanisms
- Carbohydrate Chemistry and Synthesis
- Radical Photochemical Reactions
- Receptor Mechanisms and Signaling
- Peroxisome Proliferator-Activated Receptors
- RNA modifications and cancer
- Neuroscience and Neuropharmacology Research
- Anesthesia and Sedative Agents
- Monoclonal and Polyclonal Antibodies Research
- Bipolar Disorder and Treatment
- Biochemical and Molecular Research
- Chemical Synthesis and Analysis
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010-2024
Landscape Research Group
2023
Authorised Association Consortium
2023
Alzheimer’s Disease Neuroimaging Initiative
2023
Union Bank of Switzerland
2023
Nia Association
2022
ID Genomics (United States)
2022
West Suffolk College
2017
United States Military Academy
2016-2017
NHS Lanarkshire
2001-2016
Pharmacological activation of the STING (stimulator interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report identification MSA-2, an orally available non-nucleotide human agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated stimulated interferon-β secretion in tumors, induced regression with durable antitumor immunity, synergized anti-PD-1 therapy. Experimental theoretical analyses showed...
Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed synthesized to access a previously unexplored chemical space. The assessment biochemical affinity cellular potency, along with computational, structural, biophysical characterization, was applied influence the design optimization novel STING agonists, resulting in discovery MK-1454 as molecule appropriate properties for clinical development. When administered...
The replacement of aryl rings with saturated carbocyclic structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres parasubstituted arene rings, appearing a number lead pharmaceutical candidates. However, despite value 2-substituted BCPs replacements ortho- or meta-substituted general and rapid syntheses...
A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host−guest complexes with rocuronium, these reverse muscle relaxation induced by vitro vivo therefore can be reversal agents to assist rapid recovery patients after surgery. Because this supramolecular mechanism action does not involve direct interaction cholinergic system,...
The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, tert-butyl, and alkynyl fragments order improve physicochemical properties. However, bceause of the difficulty synthesis, most BCP analogues prepared only bear 1,3-"para"-substituents. We report first selective synthesis 2,2-difluorobicyclo[1.1.1]pentanes via difluorocarbene insertion into bicyclo[1.1.0]butanes. Moreover, this methodology should inspire future studies on other...
Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia the pharmaceutical industry. Here, we describe discovery of a novel class highly potent IDO1 heme-displacing featuring unique bicyclo[1.1.1]pentane motif. Compound 1, evolving an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked desired pharmacokinetic profile due to extensive...
Oncogenic mutations in the
Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types cancers. However, low overall response rates often hamper the broad utility potential these breakthrough therapies. Combination therapy strategies currently under intensive investigation in clinic, including combination PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report discovery a class heme-binding featuring unique amino-cyclobutarene motif, which was discovered...
Compared to the abundance of methodologies accessing 1-substituted and 1,3-disubstuted bicyclo[1.1.1] pentanes (BCPs), synthetic accessibility BCPs with substitutions at methylene position has been limited. Herein, we report a selective synthesis 1-dialkylamino-2-alkylbicyclo[1.1.1]pentanes from prefunctionalized starting materials. We also achieved further functionalizations these 1,2-disubstituted developed compounds minimum necessity chromatographic purifications 1,3-dichloroacetone....
The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling progressive neurodegenerative disorder whose current therapies are limited in scope efficacy. In this report, we describe rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated the discovery of brain-penetrant, candidate-quality molecules as represented compounds 22 24. These exhibit remarkable selectivity against...
Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is negative immune regulator of T cell receptor (TCR) and B signaling that primarily expressed in hematopoietic cells. Accordingly, it has been reported HPK1 loss-of-function kinase-dead syngeneic mouse models shows enhanced cytokine production as well tumor growth inhibition vivo, supporting its value an immunotherapeutic target. Herein, we present the structurally enabled discovery novel, potent, selective...
Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy safety studies in vivo. Compound 9 showed central pharmacodynamic effects rodent models, evidenced by statistically significant increases apolipoprotein E (apoE) ATP-binding cassette transporter levels brain, along with greatly improved peripheral lipid profile when compared those full dual agonists....
Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate bicyclic piperazine sulfonamide core was designed synthesized. The resulting inhibitor containing this showed an 60-fold increase in enzyme affinity 10-fold antiviral activity relative to MK-8718.
PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression restricted to germ cells attenuation of its activity results in altered meiotic gene transcription, impairment double-stranded breaks pairing between homologous chromosomes. There growing evidence for role aberrant oncogenesis genome instability. Here we report the discovery MRK-740, potent (IC50: 80 ± 16 nM), selective cell-active inhibitor (Chemical Probe). MRK-740 binds...
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field cancer immunotherapy, upregulation IDO1 in certain cancers been linked host immune evasion and poor prognosis for patients. In particular, inhibition is combination therapy with checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, diamide class compounds was identified promising lead IDO1. While hit 1 possessed attractive cell-based potency, it suffered from...
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this compounds. Structure-based drug design strategic incorporation polarity enabled rapid improvement on potency, solubility, oxidative metabolic stability. Metabolite studies revealed that amide hydrolysis in D-pocket was...
A novel approach to chiral succinimides and derived compounds has been developed that involves lithium amide desymmetrisation of an N-ortho-tert-butylphenyl succinimide generate a putative atropisomeric intermediate enolate, alkylation which enables access the lignan lactone (+)-hinokinin.
A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of crystal structure initial lead bound to enabled optimization enzyme potency and antiviral activity. This afforded series potent orally bioavailable inhibitors which MK-8718 identified compound with favorable overall profile.
Inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization novel series potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type ATP-competitive physicochemical properties were integrated with CNS drug-like through combination structure-based drug...
Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid efficacious disease-modifying therapies. Herein, we describe invention an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, property-based drug design in concert rigorous application silico calculations presynthesis predictions enabled prioritization molecules...
We report the discovery of a benzimidazole series CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent inhibition, high selectivity versus related CYP targets, good pharmacokinetic properties in rat rhesus. In rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.