Foreword

Continuous progress in medicinal chemistry has contributed to identifying candidate compounds in drug discovery. In the 20th century, a variety of bioactive compounds were discovered and some were approved as drugs for the treatment of infectious diseases, obesity, hypertension, allergy, etc. On the other hand, biologics such as monoclonal antibodies have been recognized as an alternative powerful methodology for producing drugs in the 21st century. Recently, the number of low molecular-weight compounds approved as novel drugs has decreased because of higher hurdles for the approval of new drugs. Therefore, through advances in technology, medicinal chemists have continuously contributed to the identification of potential drug candidates for the treatment of diseases with no currently established therapeutic regimens. For the Current Topics section in this issue of the Chemical and Pharmaceutical Bulletin, we have assembled three reviews and one communication to provide useful information to medicinal chemists which could assist them in overcoming challenges in the drug discovery process.

The first review, entitled “New Gateways to the Platinum Group Metal-Catalyzed Direct Deuterium-Labeling Method Utilizing Hydrogen as a Catalyst Activator,” is by Professors Hironao Sajiki and Yoshinari Sawama and their colleagues. They summarize recent advances in the direct deuteration of sugar, saturated fatty acids, and arene derivatives using heterogeneous platinum group metals on carbon catalysts. Replacement of the hydrogen atoms by deuterium atoms is an effective strategy to improve their pharmacokinetic profiles because carbon–deuterium bonds are generally stronger than carbon–hydrogen bonds due to the isotope effect. One advantage of the methodologies described in the review is that D₂O is the cheapest, most abundant deuterium source.

The second review, “7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors,” was contributed by Mr. Takayuki Irie and Dr. Masaaki Sawa. Drug discovery targeting kinases is one of the most important topics in medicinal chemistry because of their efficacy in the treatment of cancer. Generally, kinase inhibitors bind to the ATP-binding pocket in kinase protein, and therefore classical kinase inhibitors such as staurosporine showed side effects derived from their low selectivity among kinases. Nevertheless, the kinase inhibitors approved recently have been developed as ATP competitors to interact with a hinge region in ATP-binding sites of kinases, and exhibited excellent kinase selectivity with enough safety margin. The authors describe the potential of the 7-azaindoline scaffold as a kinase-privileged moiety because 7-azaindole is a binding motif based on two hydrogen bonds with the kinase hinge region.

“Discovery and Development of Muscarinic Acetylcholine M₄ Activators as Promising Therapeutic Agents for CNS Diseases,” the third review by Dr. Kentaro Takai and Dr. Takeshi Enomoto, focuses on recent advances in drug discovery using subtype-selective M₄ muscarinic acetylcholine receptor (mAChR) activators including allosteric agonists and positive allosteric modulators. Classic mAChR agonists induced side effects due to their low selectivity toward M₂ and M₃ mAChRs. Although it is difficult to increase subtype selectivity because of high homology among M₁–M₅ mAChRs, Drs. Takai and Enomoto identified the first subtype-selective and central nervous system-penetrative M₄ mAChR agonists. These compounds improved psychosis-like behaviors in rats without inducing side effects derived from activating M₂ and M₃ mAChRs.

The communication by Professor Kaori Sakurai, “A Peptide–Glycolipid Interaction Probed by Retroinverso Peptide Analogues” gives an overview of applying the retroinverso approach to obtain novel glycolipid-binding D-peptide sequences. Glycolipid–protein interaction is an important process because it mediates a variety of cellular processes. To produce useful molecular probes, she focused on the retroinverso approach. This communication covers the design, synthesis, and evaluation of the analogues of two known GM₁-binding peptides by replacing L-amino acids with D-amino acids. As a result, the retroinverso D-peptide analogue identified also binds GM₁ as the parent L-peptide. This is a potent methodology for the design of novel peptide-based glycolipid-binding probes.

I believe that these reviews and the communication provide useful information for the design and synthesis of novel drug candidates and sincerely thank Professors Sajiki, Sawama, and Sakurai, Mr. Irie and Dr. Sawa, Dr Takai, and their colleagues for their significant contributions.