Discovery of novel 7-membered cyclic amide derivatives that inhibit 11beta-hydroxysteroid dehydrogenase type 1.

A series of novel 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27, which furthermore showed the potent efficacy in in vivo studies.

Design and synthesis of a metabolically stable and potent antitussive agent, a novel delta opioid receptor antagonist, TRK-851.

We have previously reported on antitussive effect of (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol(1b) methanesulfonate (TRK-850), a selective delta opioid receptor antagonist which markedly reduced the number of coughs in a rat cough model. We designed TRK-850 based on naltrindole (NTI), a typical delta opioid receptor antagonist, to improve its permeability through the blood-brain barrier by introducing hydrophobic moieties to NTI. The ED(50) values of NTI and compound 1b by intraperitoneal injections were 104 microg/kg and 2.07 microg/kg, respectively. This increased antitussive potency probably resulted from the improved brain exposure of compound 1b. However, 1b was extremely unstable toward metabolism by cytochrome P450. In this study, we designed and synthesized compound 1b derivatives to improve the metabolic instability, which resulted in affording highly potent and metabolically stable oral antitussive agent (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8'-fluoro-5',6'-dihydro-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-3,14-diol (1c) methanesulfonate (TRK-851).

Structure-antitussive activity relationships of naltrindole derivatives. Identification of novel and potent antitussive agents.

We have previously reported antitussive effects of naltrindole (NTI), a typical delta opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104 microg/kg and 1840 microg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has micro agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a delta opioid antagonist, its derivatives have potential as highly potent antitussives, free from the mu opioid agonist side effects. We attempted to optimize the NTI derivatives to develop novel antitussive agents. On the basis of the studies of structure-antitussive activity relationships of alkyl substituted NTI derivatives, we designed NTI derivatives with extra ring fused structures. As a clinical candidate, we identified a highly potent new compound, (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 microg/kg).

[Future directions of anticancer drug development in Japan].

At the 13th Oncology Forum, future directions of anticancer drug development in Japan were discussed. Development of anticancer drugs in the 1990s was based on the concept of total cell kill, but now development of molecular targeted drugs becomes the mainstream. Unfortunately, molecular targeted drugs and antibody agents are mostly foreign products and translational research in Japan is poor as it stands now. As future directions of anticancer drug development, international collaborative development is considered essential, but there are various obstacles to the conduct of international collaborative studies. Companies, medical institutions and regulatory agencies must make collaborative efforts to overcome these obstacles. As future development of anticancer agents in individual cancer regions in Japan is considered, gastric cancer therapy is progressing considerably with the advent of S-1 and in the future, development of multi-agent combination therapy including molecular targeted agents is expected. Much progress in colon cancer therapy has been made owing to accumulation of evidence in recent years. Multi-agent chemotherapy combined with antibody agent, which is advancing overseas, is introduced to Japan. Clinical development of combination therapy with a high therapeutic index, including compounds discovered in Japan, is expected in the future. Although conventionally hormone therapy has been considered as first-line treatment of breast cancer and used in combination with chemotherapy, with the advent of antibody agents in recent years, HER2 sensitivity has greatly affected the algorithm of treatment. Future development of molecular targeted drugs and individualised diagnosis using cDNA array, etc. are likely to advance individualisation of treatment. On the other hand, large-scale clinical trials are required to prove a small difference in adjuvant therapy, etc. and accordingly international studies are becoming indispensable. For urological cancers, molecular targeted drugs have been proved effective in renal cancer and future development of molecular targeted drugs for prostate cancer and testicular tumors is desirable. At that time, elucidation of the mechanism of action of molecular targeted drug and strategic drug development designed to increase its efficacy are expected. As a future direction of anticancer drug development, there are many cancers in whose international collaborative studies Japan can participate. Studies of prostate cancer and renal cell carcinoma can be internationalised while internationalisation of studies in ovarian and pancreatic cancers is essential. Phase III should be performed as international collaborative studies and depending on the type of cancer and drug, collaborative studies in an Asian region are effective. When participating in an international collaborative study, Japan needs to recruit subjects at a speed similar to the rest of the world, but differences in medical environment including clinical trials pose a problem. To solve this problem, it is considered effective not only to pursue the Western environment but also to improve staff such as nurses and CRC. The number of Japanese patients necessary for Phase III studies is individual developmental strategy and needs to be examined by both companies and regulatory agencies.