8 research outputs found
Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base-Sensitive 6‑Bromoisoquinoline-1-carbonitrile with (<i>S</i>)‑3-Amino-2-methylpropan-1-ol
This
work describes the optimization and scale-up of a Buchwald–Hartwig
amination reaction for the preparation of a pharmaceutical intermediate.
This C–N bond formation is challenged by the use of a chiral
primary amine, which both adds cost and favors formation of biaryl
byproducts. In order to develop a scalable process, a number of factors
had to be investigated including catalyst selection and stoichiometry
of the chiral amine. These all needed to be optimized while maintaining
low palladium levels in the isolated product. The reaction was found
to be most effective using PdÂ(dba)<sub>2</sub> with BINAP and Cs<sub>2</sub>CO<sub>3</sub> in THF. When executed on 2.5 kg scale, these
conditions provided 2.06 kg of the desired product in 80% yield with
only 73 ppm residual palladium. To date, this process has been successfully
executed to produce more than 12 kg of compound <b>(</b><i><b>S</b></i><b>)-3</b>
Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain
Chemical
probes are required for preclinical target validation
to interrogate novel biological targets and pathways. Selective inhibitors
of the CREB binding protein (CREBBP)/EP300 bromodomains are required
to facilitate the elucidation of biology associated with these important
epigenetic targets. Medicinal chemistry optimization that paid particular
attention to physiochemical properties delivered chemical probes with
desirable potency, selectivity, and permeability attributes. An important
feature of the optimization process was the successful application
of rational structure-based drug design to address bromodomain selectivity
issues (particularly against the structurally related BRD4 protein)
1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators
Structure-Based Approach To Identify 5‑[4-Hydroxyphenyl]Âpyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators
In an effort to find
new and safer treatments for osteoporosis
and frailty, we describe a novel series of selective androgen receptor
modulators (SARMs). Using a structure-based approach, we identified
compound <b>7</b>, a potent AR (ARE EC<sub>50</sub> = 0.34 nM)
and selective (N/C interaction EC<sub>50</sub> = 1206 nM) modulator.
In vivo data, an AR LBD X-ray structure of <b>7</b>, and further
insights from modeling studies of ligand receptor interactions are
also presented
Structure-Based Approach To Identify 5‑[4-Hydroxyphenyl]Âpyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators
In an effort to find
new and safer treatments for osteoporosis
and frailty, we describe a novel series of selective androgen receptor
modulators (SARMs). Using a structure-based approach, we identified
compound <b>7</b>, a potent AR (ARE EC<sub>50</sub> = 0.34 nM)
and selective (N/C interaction EC<sub>50</sub> = 1206 nM) modulator.
In vivo data, an AR LBD X-ray structure of <b>7</b>, and further
insights from modeling studies of ligand receptor interactions are
also presented
Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects
Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br /
1‑(2-Hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators
We
present a novel series of selective androgen receptor modulators
(SARMs) which shows excellent biological activity and physical properties.
1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitriles
showed potent binding to the androgen receptor (AR) and activated
AR-mediated transcription in vitro. Representative compounds demonstrated
diminished activity in promoting the intramolecular interaction between
the AR carboxyl (<i>C</i>) and amino (<i>N</i>) termini. This <i>N</i>/<i>C</i>-termini interaction
is a biomarker assay for the undesired androgenic responses in vivo.
In orchidectomized rats, daily administration of a lead compound from
this series showed anabolic activity by increasing levator ani muscle
weight. Importantly, minimal androgenic effects (increased tissue
weights) were observed in the prostate and seminal vesicles, along
with minimal repression of circulating luteinizing hormone (LH) levels
and no change in the lipid and triglyceride levels. This lead compound
completed a two week rat toxicology study, and was well tolerated
at doses up to 100 mg/kg/day, the highest dose tested, for 14 consecutive
days