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)­phthalimides. 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 ED₅₀ 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 S1P₁ 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 S1P₁ 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 (S1P₁) 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 S1P₁ is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P₁ 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 S1P₁ with selectivity over S1P₃ 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