A5014604690- Neuroscience and Neuropharmacology Research
- Synthesis and Biological Evaluation
- Phenothiazines and Benzothiazines Synthesis and Activities
- Estrogen and related hormone effects
- HER2/EGFR in Cancer Research
- Receptor Mechanisms and Signaling
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Pharmacological Receptor Mechanisms and Effects
- Cancer therapeutics and mechanisms
- Inflammatory mediators and NSAID effects
- Memory and Neural Mechanisms
- Amino Acid Enzymes and Metabolism
- Advanced Breast Cancer Therapies
- DNA Repair Mechanisms
- Synthesis and Catalytic Reactions
- Synthesis and Reactivity of Heterocycles
- Medicinal Plants and Bioactive Compounds
- Synthesis of β-Lactam Compounds
- Protein Kinase Regulation and GTPase Signaling
- Psoriasis: Treatment and Pathogenesis
- Herbal Medicine Research Studies
- NF-κB Signaling Pathways
- 14-3-3 protein interactions
- Nicotinic Acetylcholine Receptors Study
Charles River Laboratories (United Kingdom)
2015-2021
Charles River Laboratories (Netherlands)
2014
MSD (UK) Limited (United Kingdom)
1999-2010
Merck & Co., Inc., Rahway, NJ, USA (United States)
2000-2006
Breast cancer remains a leading cause of death in women, representing significant unmet medical need. Here, we disclose our discovery efforts culminating clinical candidate, 35 (GDC-9545 or giredestrant). is an efficient and potent selective estrogen receptor degrader (SERD) full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing preclinical...
The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing receptors are diazepam, whereas anxiogenic an alpha3-selective inverse agonist selective this subtype should be anxiolytic. We have extended latter pharmacological approach to identify a compound,...
It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole and reduced pKa piperazines compared to piperidines may be one possible explanation for these differences. To investigate this proposal we developed versatile synthetic strategies incorporation fluorine into ligands, producing novel 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, both piperazine...
A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog functional selectivity for the GABA(A)alpha2 -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g 7-propan-2-olimidazopyrimidine 14k are anxiolytic both conditioned unconditioned animal models anxiety minimal sedation observed at full BZ binding site occupancy.
The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists is described. By investigation the optimal position for basic nitrogen in a series 2-phenyl-3-piperidylindoles, it was found that with at 3-position piperidine not necessary to further substitute order obtain good binding receptors. This meant compounds no longer had affinity IKr potassium channel, an issue previous 2-aryl-3-(4-piperidyl)indoles. Improvements could be made oral bioavailability...
Non-selective benzodiazepines, such as diazepam, interact with equivalent affinity and agonist efficacy at GABA A receptors containing either an α1, α2, α3 or α5 subunit. However, which of these particular subtypes are responsible for the anticonvulsant effects diazepam remains uncertain. In present study, we examined ability to reduce pentylenetetrazoLe (PTZ)-induced maximal electroshock (MES)-induced seizures in mice point mutations single (α1H101R, α2H101R α5H105R) multiple (α125H→R) α...
Inhalation of a Janus kinase 1 inhibitor suppressed lung inflammation without systemic side effects in rodent models asthma.
Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant FDA-approved to treat ER+ cancer and works through two mechanisms—as full antagonist selective estrogen degrader (SERD)—but lacks oral bioavailability. Thus, we envisioned "best-in-class" molecule with the same dual mechanisms as fulvestrant, but significant exposure. Through lead optimization, discovered tool 12 (GNE-149) improved degradation antiproliferative activity in both MCF7...
The identification of a series imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to clinical candidate, 11. Compound 11 shows good bioavailability half-life in preclinical species, it nonsedating anxiolytic both rat squirrel monkey behavioral models.
Amalgamation of the structure-activity relationship two series GlyT1 inhibitors developed at Merck led to discovery a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy transporters rhesus monkey as determined by displacement PET tracer ligand.
Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads hypothesis that inhibition of ChK1 might enhance effectiveness DNA-damaging therapies treatment cancer. Lead compound (GNE-783), prototype 1,7-diazacarbazole class inhibitors, was found be highly potent inhibitor acetylcholine esterase (AChE) and unsuitable development. A campaign analogue synthesis established SAR delineating AChE...
A rearrangement reaction involving the indole nucleus was investigated using stereochemical markers and low-temperature NMR experiments. Treatment of (3S,4S)-3-hydroxy-4-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with diethylaminosulfur trifluoride gave stereospecifically (3S,4S)-4-fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic complete regioselectivity. The initial formation a reactive spirocyclopropyl-3H-indole intermediate is believed to be...
Clinically effective antimigraine drugs such as Sumatriptan have similar affinity at h5-HT1D and h5-HT1B receptors. In the search for a h5-HT1D-selective agonist an agent, novel series of 3-(propylpiperazinyl)indoles been synthesized evaluated This class compounds has provided subnanomolar, fully efficacious agonists with up to 200-fold selectivity receptor over receptor. Unlike other series, several propylpiperazines demonstrate good oral bioavailability. The optimum compound was...