Hitoshi Ohki

Discovery of DF-461, a Potent Squalene Synthase Inhibitor

We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure-activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies.

Systematic research of peptide spacers controlling drug release from macromolecular prodrug system, carboxymethyldextran polyalcohol-peptide-drug conjugates.

The primary purpose of this study was to comprehensively delineate specificity of the peptide spacer sequence to tumor-expressed proteases for the design of macromolecular carrier-peptide spacer-drug conjugate system. 225 conjugates of carboxymethyldextran polyalcohol (CM-Dex-PA) as water-soluble carrier and a dansyl derivative (N-(4-aminobutyl)-5-(dimethylamino)-1-naphthalenesulfonamide, DNS) as the model drug linked with different tetrapeptide spacers (Gly-Gly-P(2)-P(1), P(2), P(1): Ala, Asn, Gly, Cit, Gln, Ile, Leu, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) were combinatorially synthesized. First, the drug release assay of all of the fluorogenic model conjugates was performed in murine Meth A solid tumor homogenates. The drug release rate was higher with conjugates having hydrophobic amino acids at P(2). It was also found that conjugates with Asn release the drug rapidly and, in contrast, those with Pro does not. Second, we selected three peptide spacers (Gly-Gly-Phe-Gly, Gly-Gly-Ile-Gly, Gly-Gly-Pro-Leu), which release only DNS at different rates, and applied them to doxorubicin (DXR) conjugates. These three DXR conjugates were used for investigating relationships with drug release, pharmacokinetics, and antitumor activity against Meth A bearing mice of these conjugates. The release of DXR from the conjugates corresponded well with that of DNS conjugates in tumor homogenates. CM-Dex-PA-Gly-Gly-Phe-Gly-DXR and CM-Dex-PA-Gly-Gly-Ile-Gly-DXR indicated strong antitumor activity, with the comparable pharmacokinetic profile of released DXR in tumor. Taken with the fact that the drug release rate in tumor homogenates was approximately 10-fold different between these two DXR conjugates, it is likely that cellular uptake of the conjugate would be rate-limiting, rather than the drug release process under the in vivo situation. However, much weaker antitumor activity was observed with CM-Dex-PA-Gly-Gly-Pro-Leu-DXR, of which the drug release was extremely slow.

Discovery of novel tricyclic compounds as squalene synthase inhibitors

In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.

Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria.

A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4-6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.

Correction to “Discovery of DF-461, a PotentSqualene Synthase Inhibitor”.

According to the recent reconsideration and re-evaluation of every author’s contribution of this work, all of authors have reached the final conclusion that we should rearrange the order of the authors and remove Dr. Usui from the author list as observed below. “Masanori Ichikawa,* Masami Ohtsuka, Hitoshi Ohki, Masahiro Ota, Noriyasu Haginoya, Masao Itoh, Yoshihiro Shibata, Kazuyuki Sugita, Yutaka Ishigai, Koji Terayama, Akira Kanda, and Hiroyuki Usui” to “Masanori Ichikawa,* Masami Ohtsuka, Hitoshi Ohki, Masahiro Ota, Noriyasu Haginoya, Masao Itoh, Yoshihiro Shibata, Yutaka Ishigai, Koji Terayama, Akira Kanda, and Kazuyuki Sugita.” All of authors have already approved this correction. Dr. Usui, our supervisor, also authorized and approved it.