Otsuka Pharmaceutical Development & Commercialization, Inc.
3,4-dihyrdocarbostyril derivative CAS 1883747-71-4
Chemical Class:
3,4-dihydrocarbostyril derivative

February 3, 2022. Phase 2 study posted in Clinical NCT05221502 Safety and efficacy of 4 months combination treatment for patients with drug sensitive TB:

    Delamanid + Bedaquiline + OPC-167832 10 mg

    Delamanid + Bedaquiline + OPC-167832 30 mg

    Delamanid + Bedaquiline + OPC-167832 90 mg

October 2021. Poster Presentation. TB Science / 52nd UNION virtual meeting. POSTER #TBS EP 25: A Phase 1, randomized, double blind, placebo controlled trial in healthy subjects to assess tolerability, pharmacokinetics, and food effects of single ascending doses of OPC167832.  Key findings:
• OPC 167832 was well tolerated at all single doses up to 480 mg, with no serious adverse events or adverse events leading to     discontinuation
• Pharmacokinetic parameters:
  • Median t max ranged from 2.5 to 3.5 hours
  • C max increased with dose and appeared to plateau up to 60 mg, then increased dose proportionally from 90 480 mg
  • AUC inf increased dose proportionally up to 240 mg
  • Median t ½ ranged from 18 40 hours across cohorts
• Minimal differences in C max and AUC inf were observed following standard or high fat meals compared to the fasted state

August 9, 2021. Press Release. Otsuka Awarded Grant for Phase 2 Trial Combining Novel Anti-Tuberculosis Compound OPC-167832 with Delamanid and Bedaquiline from the Bill & Melinda Gates Foundation. Expected to begin in 2022 with results available in 2024.  NCT05221502

August 2021. Publication.  Robertson et al. Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 inhibitors TBA-7371, PBTZ169 and OPC-167832. Antimicrob Agents Chemother August 9; AAC0058321. Advance online publication. PMC8522729  

May 2020. Publication. Hariguchi et al.  OPC-167832, a novel carbostyril derivative with potent anti-tuberculosis activity as a DprE1 inhibitor.  Antimicrob Agents Chemother May 21;64(6):e02020-19. PMID: 32229496

June 2018. Two posters on OPC-167832 were presented at the ASM Microbe 2018 conference in Atlanta, GA June 10, 2018. 

SUNDAY - 543. OPC-167832, A Newly Synthesized Carbostyril Derivative, is A Promising Anti-Tuberculosis Drug Candidate to Improve Tuberculosis Treatment

N. Hariguchi1, X. Chen1, M. Matsuba1, Y. Hayashi1, M. Fujiwara1, Y. Ohba1, Y. Kawano2, H. Shimizu2, M. Matsumoto3, K. Inagaki1; 1Infectious Diseases Unit, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan, 2Med.l Chemistry Res. Lab., Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan, 3Pharmaceutical Business Div., Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan

OPC-167832 is a newly synthesized carbostyril derivative which shows anti-mycobacterial activity by inhibiting decaprenylphosphoryl-β-D-ribose 2’-oxidase (DprE1), an essential enzyme for cell wall biosynthesis of Mycobacterium tuberculosis (MTB). The minimum inhibitory concentrations of OPC-167832 against MTB on both laboratory strains and clinically isolated strains including multidrug resistant/extensively drug resistant MTB ranged from 0.00024 to 0.002 μg/mL. OPC-167832 showed potent bactericidal activity against both growing and intracellular bacilli and therapeutic effect in an experimental mouse model of chronic TB at lower doses than other anti-TB drugs. OPC-167832 did not show antagonistic effects with the other anti-TB drugs in in vitro checkerboard agar dilution method and in a mouse model of chronic TB. Furthermore, OPC-167832 in regimens combined with delamanid showed superior efficacies to a standard regimen RHZE (rifampicin + isoniazid + pyrazinamide + ethambutol) in mice. We concluded that OPC-167832 is a new anti-TB drug candidate and could be a member of new generation anti-TB regimens which have potential to shorten the period of TB treatment.

SUNDAY - 555. OPC-167832, A New Potent Anti-Tuberculosis Drug Candidate, Kills Mycobacterium Tuberculosis By Inhibiting the Synthesis of Cell-Wall Arabinans

X. Chen1, Y. Hayashi1, M. Fujiwara1, N. Hariguchi1, Y. Kawano2, H. Shimizu2, M. Matsumoto3, K. Inagaki1; 1Infectious Diseases Unit, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan, 2Med.l Chemistry Res. Lab., Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan, 3Pharmaceutical Business Div., Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan

Here we report OPC-167832, a newly synthesized carbostyril derivative which is currently tested in clinical trials, shows strong activity against MTB in vitro. By genomic DNA analysis of its laboratory-isolated resistant strains, we identified the mutations of two genes (rv0678 and rv3790) are responsible for the resistance of OPC-167832. We have generated several M bovis BCG Tokyo strains overexpressing mutated rv3790 genes and found them to confer resistance to OPC-167832. We also confirmed that OPC-167832 inhibited the enzyme activity of recombinant wildtype DprE1 from a BCG strain. These results suggest that OPC-167832 kills MTB by the inhibition of DprE1, which abolishes the formation of a key precursor for the synthesis of arabinans on the cell wall of MTB.

2016. During the 47th Union World Conference on Lung Health in Liverpool, U.K. (October 2016), Otsuka reported it is developing OPC-167832 in combination with delamanid. OPC- 167832 is intended to target both drug-susceptible as well as drug-resistant forms of TB, and has a different mechanism of action than all currently approved anti-TB drugs. MIC for M. tuberculosis 0.00024 to 0.002 ug/ml. Mouse models of chronic TB studies showed that delamanid and OPC-167832, along with one or two other new anti-TB drugs, are more effective than standard regimens against both drug-susceptible as well as multidrugresistant TB. Early results suggest that regimens with OPC-167832 and delamanid at the core could potentially shorten treatment duration and improve treatment outcomes. The US FDA has already granted the investigation of OPC-167832 a Fast Track status, and human trials are underway.