Medicinal Chemistry of Oligonucleotide Drugs - Milestones of the Past and Visions for the Future.

The oligonucleotide therapeutics field has blossomed in recent years, with thirteen approved drugs today and the promise of accelerated growth in coming years. Much of the progress in this field is due to advances in the medicinal chemistry of oligonucleotides,combined with a judicious choice of molecular targets and disease areas. In this perspective, we describe the growth of this new class of drugs highlighting selected milestones in oligonucleotide medicinal chemistry.

Nickel-Catalyzed Selective Reduction of Carboxylic Acids to Aldehydes.

The direct reduction of carboxylic acids to aldehydes is a fundamental transformation in organic synthesis. The combination of an air-stable Ni precatalyst, dimethyl dicarbonate as an activator, and silane reductant effects this reduction for a wide variety of substrates, including pharmaceutically relevant structures, in good yields and with no overreduction to alcohols. Moreover, this methodology is scalable, allows access to deuterated aldehydes, and is also compatible with one-pot utilization of the aldehyde products.

The pregnane X receptor down-regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for ("squelching") SRC-1 coactivator.

Background And Purpose: The organic cation transporter 1 (OCT1) transports cationic drugs into hepatocytes. The high hepatic expression of OCT1 is controlled by the HNF4α and USF transcription factors. Pregnane X receptor (PXR) mediates induction of the principal xenobiotic metabolizing enzymes and transporters in the liver.