5 research outputs found
Organocatalyzed, Visible-Light Photoredox-Mediated, One-Pot Minisci Reaction Using Carboxylic Acids via <i>N</i>‑(Acyloxy)phthalimides
An
improved, one-pot Minisci reaction has been developed using
visible light, an organic photocatalyst, and carboxylic acids as radical
precursors via the intermediacy of in situ-generated <i>N</i>-(acyloxy)Âphthalimides. The conditions employed are mild, demonstrate
a high degree of functional group tolerance, and do not require a
large excess of the carboxylic acid reactant. As a result, this reaction
can be applied to drug-like scaffolds and molecules with sensitive
functional groups, enabling late-stage functionalization, which is
of high interest to medicinal chemistry
Antroquinonol A: Scalable Synthesis and Preclinical Biology of a Phase 2 Drug Candidate
The
fungal-derived Taiwanese natural product antroquinonol A has attracted
both academic and commercial interest due to its reported exciting
biological properties. This reduced quinone is currently in phase
II trials (USA and Taiwan) for the treatment of non-small-cell lung
carcinoma (NSCLC) and was recently granted orphan drug status by the
FDA for the treatment of pancreatic cancer and acute myeloid leukemia.
Pending successful completion of human clinical trials, antroquinonol
is expected to be commercialized under the trade name Hocena. A synthesis-enabled
biological re-examination of this promising natural product, however,
reveals minimal <i>in vitro</i> and <i>in vivo</i> antitumor activity in preclinical
models
Improving the Pharmacokinetic and CYP Inhibition Profiles of Azaxanthene-Based Glucocorticoid Receptor ModulatorsIdentification of (<i>S</i>)‑5-(2-(9-Fluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)‑5<i>H</i>‑chromeno[2,3‑<i>b</i>]pyridin-5-yl)-2-methylpropanamido)‑<i>N</i>‑(tetrahydro‑2<i>H</i>‑pyran-4-yl)-1,3,4-thiadiazole-2-carboxamide (BMS-341)
An
empirical approach to improve the microsomal stability and CYP
inhibition profile of lead compounds <b>1a</b> and <b>1b</b> led to the identification of <b>5</b> (BMS-341) as a dissociated
glucocorticoid receptor modulator. Compound <b>5</b> showed
significant improvements in pharmacokinetic properties and, unlike
compounds <b>1a</b>–<b>b</b>, displayed a linear,
dose-dependent pharmacokinetic profile in rats. When tested in a chronic
model of adjuvant-induced arthritis in rat, the ED<sub>50</sub> of <b>5</b> (0.9 mg/kg) was superior to that of both <b>1a</b> and <b>1b</b> (8 and 17 mg/kg, respectively)
Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P<sub>1</sub> Receptor Modulator in Clinical Trials
Clinical
validation of S1P receptor modulation therapy was achieved
with the approval of fingolimod (Gilenya, <b>1</b>) as the first
oral therapy for relapsing remitting multiple sclerosis. However, <b>1</b> causes a dose-dependent reduction in the heart rate (bradycardia),
which occurs within hours after first dose. We disclose the identification
of clinical compound BMS-986104 (<b>3d</b>), a novel S1P<sub>1</sub> receptor modulator, which demonstrates ligand-biased signaling
and differentiates from <b>1</b> in terms of cardiovascular
and pulmonary safety based on preclinical pharmacology while showing
equivalent efficacy in a T-cell transfer colitis model
Identification of Tricyclic Agonists of Sphingosine-1-phosphate Receptor 1 (S1P<sub>1</sub>) Employing Ligand-Based Drug Design
Fingolimod (<b>1</b>) is the
first approved oral therapy
for the treatment of relapsing remitting multiple sclerosis. While
the phosphorylated metabolite of fingolimod was found to be a nonselective
S1P receptor agonist, agonism specifically of S1P<sub>1</sub> is responsible
for the peripheral blood lymphopenia believed to be key to its efficacy.
Identification of modulators that maintain activity on S1P<sub>1</sub> while sparing activity on other S1P receptors could offer equivalent
efficacy with reduced liabilities. We disclose in this paper a ligand-based
drug design approach that led to the discovery of a series of potent
tricyclic agonists of S1P<sub>1</sub> with selectivity over S1P<sub>3</sub> and were efficacious in a pharmacodynamic model of suppression
of circulating lymphocytes. Compound <b>10</b> had the desired
pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated
maximal efficacy when administered orally in a rat adjuvant arthritis
model