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  • From our in vivo studies

    2023-11-30

    From our in vivo studies and previously reported findings [25], we have found that orteronel possesses excellent oral BA. Indeed, single oral dosing of orteronel at doses of 0.3–10.0mg/kg decreased serum DHEA levels in a dose-dependent manner. Of interest, DHEA levels did not return to levels comparable to that observed in the vehicle-treated group until approximately 48h after orteronel dosing. Conversely, at the 1mg/kg dose, testosterone levels did reach and briefly exceed pre-treatment levels at 24h. However, this might have Rofecoxib resulted from an increased LH level, and potentially suggest that more regular dosing or higher doses than 1mg/kg may be required to maintain testosterone suppression. Studies to more clearly define tissue distribution and clearance are under consideration to better define the pharmacological basis of this extended activity and help inform our ongoing clinical program. For recurrent prostate cancer after radical prostatectomy, hormone ablation therapy remains the mainstay of medical treatment. However, prostate cancer inevitably acquires resistance to this approach. While several molecular and/or cellular mechanisms have been proposed to be responsible for this resistance [6], [7], [8], [10], [11], [12], [13], [14], [15], [49], [50], it is clear that circulating androgens drive prostate cancer progression, even following surgical or medical castration. Thus reductions in residual testosterone after castration may be an effective treatment for some CRPCs. Currently, anti-androgens such as bicalutamide, in combination with castration, are used to block the action of the residual androgens. However, treatment with bicalutamide often leads to the emergence of resistance possibly associated with the over-expression of the AR or AR co-factors [8], [9], [51], or the emergence of mutated AR [13], [14]. Based on the encouraging data seen in phase 1/2 clinical trials of abiraterone acetate, a steroidal Rofecoxib that inhibits both 17,20-lyase and 17-hydroxylase activities of CYP17A1 [48], [52], [53], the progression of a significant proportion of CRPC may depend on extra-gonadal androgen production [23], [24], [54], [55], [56]. In this study, we show that orteronel, by virtue of its enzyme specificity and potency might be an alternate therapeutic option to suppress circulating levels of residual androgens and consequently inhibit the progression of CRPC while inducing minimal off-target effects on other CYP metabolizing enzymes [25]. To this end, the safety and efficacy of orteronel is currently being investigated in phase 1/2 clinical trials in patients with metastatic CRPC.
    Disclosure statement/funding All authors are employees of Takeda Pharmaceutical Company Limited, thus the work was supported in full by Takeda Pharmaceutical Company Limited.
    Acknowledgments We thank H. Shinohara and Y. Akinaga for technical assistance and Dr F.W. Dahlquist (University of Oregon) for kindly providing vector pCWori. Some of the animal experiments were conducted at Shin Nippon Biomedical Laboratories, Kagoshima, Japan, and Keari Inc., Wakayama, Japan. The authors would also like to thank Dr. James Darnowski for critical reading and valuable advice and Catherine Crookes of FireKite for editing assistance in the development of this manuscript, which was supported by funding from Millennium Pharmaceuticals, Inc.
    Introduction Ionic liquids (ILs) are environmentally friendly alternatives of organic solvents due to their low melting point, good chemical stability and high solubility in polar organic and inorganic compounds. Basic ILs can play the dual role of reaction medium and catalyst, replacing traditional base catalysts such as KOH or NaOH [1]. Aza-Michael reactions are usually carried out using transition metal salts and complexes or Brønsted acids as catalysts [2]. These methods have many drawbacks due to the high price and toxicity of catalysts, therefore the attention was focused on mild, environmentally benign processes. In addition, earlier studies prove that amines exhibit higher nucleophilicity in ionic liquids than in organic solvents [3]. Accordingly, 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) derived ionic liquids were found to be efficient catalysts in aza-Michael addition of aliphatic [4] and aromatic amines [5] to produce α,β-unsaturated ketones under solvent-free conditions. In case of aliphatic amines the ionic liquid was reused without significant loss of activity [4]. Imidazolium and DABCO based ionic liquids were also found to promote aza-Michael addition of different N-nucleophiles to α,β-unsaturated compounds [6], [7].