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  • The syntheses of a and b are

    2024-02-28

    The syntheses of 27a and 27b are shown in Scheme 5. Substituted naphthalene 21c was brominated using N-bromosuccinimide (NBS) and 2,2′-azobis(2-methylpropionitrile) (AIBN) to yield 25, which was subjected to lactam cyclization to form 26a and 26b, respectively. Deprotections of each EX527 yielded the desired 27a and 27b. The regioisomers 30a and 30b were also synthesized from 21d in a similar manner, as shown in Scheme 6. To examine the stereochemical requirement at the chiral centers of these inhibitors, optical resolutions of 27a and 27b into (−)-27a and (+)-27a, and (−)-27b and (+)-27b, respectively, were performed using preparative HPLC with a Chiralpak AD column. Additionally, as shown in Scheme 7, (+)-27b was converted to the 4-bromobenzenesulfonyl derivative 31 and the absolute configuration of (+)-27b was confirmed to be R by X-ray crystallographic analysis of 31, as shown in Figure 2.
    Results and discussion
    Conclusions We have successfully synthesized a new class of potent and selective 17,20-lyase inhibitors. Replacement of the substituent at the 6-position of the naphthalene ring showed that a methylcarbamoyl group was optimal in terms of potency and selectivity. Further modifications aimed at fixing the orientation of the carbonyl group of the inhibitor yielded tricyclic compounds 27a and EX527 27b that were potent and selective human 17,20-lyase inhibitors. Among them (−)-27b showed good selectivity (>1000-fold) for the inhibition of 17,20-lyase over CYP3A4, while showing potent inhibitory activity against 17,20-lyase. Additional biological evaluation revealed that (−)-27b exhibited potent in vivo efficacy at an oral dose of 1mg/kg in monkeys and showed favorable pharmacokinetic profiles when administered to rats. Further evaluation on this series is ongoing, with the aim of identifying a new potent and highly selective 17,20-lyase inhibitor.
    Experimental Melting points were determined using a BUCHI Melting Point B-545 apparatus and are uncorrected. Infrared (IR) spectra were taken using a SHIMADZU FT-IR-8200PC spectrometer. 1H NMR spectra were recorded using a Varian Gemini-200, Varian Mercury-300 spectrometer, or a Bruker AVANCE-300 spectrometer. 13C NMR spectra were recorded using a Bruker AVANCE-300 spectrometer; chemical shifts are given in ppm with tetramethylsilane as an internal standard, and coupling constants (J) are measured in hertz (Hz). The following abbreviations are used: s=singlet, d=doublet, t=triplet, m=multiplet, br s=broad singlet. LCMS was performed on the Agilent1200Sl and Agilent6130MS apparatus with 5mM aqueous AcONH4 solution/acetonitrile mobile phase. Reactions were followed by TLC on Silica Gel 60 F254 precoated TLC plates (Merck, Darmstadt, Germany). Column chromatography was performed using Silica Gel 60 (E. Merck, Darmstadt, Germany). Compounds 3 (Kaku, T. et al., manuscript in preparation) and 13 were prepared in the same manner as described previously.
    Acknowledgments
    Introduction The prostate is an androgen-dependent organ and androgens are essential for growth and maintenance of prostate function. As around 80% of patients with prostate cancer respond to hormonal ablation, the current standard treatment for prostate cancer is surgical castration or medical castration, which involves the administration of luteinizing hormone–releasing hormone (LH–RH) agonists such as leuprorelin or goserelin. In the past decade, combination therapy of an LH–RH agonist with an anti-androgen, referred to as maximum androgen blockade (MAB), has also been used in the medical treatment of advanced prostate cancer. However, unfavorable effects of anti-androgens such as anti-androgen withdrawal syndrome have been observed in some clinical cases. Additionally, recent studies have suggested Malpighian tubules residual adrenal androgens remaining after castration could be responsible for the development of castration-resistant prostate cancer. 17,20-Lyase, also known as CYP17A1, is a key enzyme in androgen biosynthesis that has been proposed as an alternative therapeutic target for prostate cancer to address some of these issues.6, 7, 8 To date, several steroidal and nonsteroidal inhibitors of 17,20-lyase9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 have been reported, of which a few, for example, YM-116 and abiraterone acetate (Fig. 1), have been evaluated in clinical studies. The structural features of these inhibitors include a lipophilic moiety such as a steroidal skeleton or a steroid mimetic fused ring with a heteroaromatic ring, which may bind heme iron in the targeted enzyme.