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  • CYP A is one of the

    2024-05-27

    CYP3A4 is one of the key metabolizing A-674563 of the cytochrome P450 (CYP) superfamily of heme-containing monooxygenases. As the CYP family of enzymes plays important roles not only in the xenobiotic metabolism and detoxification of a large number of drugs, but also in the biosynthesis of endogenous steroids, CYP inhibitors have potential risk to induce drug–drug interactions or significant systemic side effects. Therefore, high specificity and selectivity for 17,20-lyase over the other CYPs is an important requirement for clinical use. Here, we report the design, synthesis and biological activities of the novel 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivatives and related compounds as highly selective 17,20-lyase inhibitors. In addition, we discuss our observations on achieving high selectivity over other CYP enzymes for (+)-3c.
    Results and discussion
    Conclusions We have successfully synthesized a new class of 17,20-lyase inhibitor. As a result of incorporating the fused imidazole ring system, (+)-3c was identified as a potent and highly selective inhibitor of 17,20-lyase. Further biological evaluation of (+)-3c revealed it to be associated with potent reductions in both serum testosterone and DHEA concentrations in monkeys administered a 1mg/kg dose of (+)-3c. Furthermore, molecular modeling and general consideration for CYP enzymes suggests that the structural and physicochemical properties of (+)-3c, such as conformational rigidity and low ClogP value, may account for the observed selectivity for 17,20-lyase over other CYP enzymes. In general, ring systems such as imidazole and pyridine rings are known to be good ligands for heme iron, which is found in the CYP enzymes. Therefore, difficulties are often encountered when developing CYP inhibitors with these rings owing to their ability to bind nonselectively to heme iron found in the CYP enzymes. We believe that these findings regarding the selectivity of (+)-3c over the CYPs could be applied to other series of CYP inhibitors and our approach to (+)-3c may provide a new methodology in this field. Finally, (+)-3c (orteronel [TAK-700]) was selected as a candidate for further development and is currently being evaluated in patients in phase III clinical trials for the potential treatment of prostate cancer.
    Experimental
    Acknowledgments
    Introduction The prostate is a gland of the male reproductive system, located beneath the bladder and surrounding the upper part of the urethra, whose mainly role is to secrete a slightly acidic fluid, milky or white in appearance, that usually constitutes 50–75% of the volume of the semen. This gland is an androgen-dependent organ and thus androgens are essential for its growth and function [1]. Androgenic hormones, in particular testosterone (9 or T) and 5α-dihydrotestosterone (10 or DHT) (Scheme 1), exert their effects in the prostate through binding to the androgen receptor (AR), initiating transcription, which triggers the synthesis of specific proteins and also cell proliferation [1], [2]. About 90–95% of the circulating androgens are produced in the testes and the remaining 5–10% are synthesized in the adrenals [3]. Benign prostatic hyperplasia (BPH) and prostatic cancer (PC) are extremely common age-related proliferative diseases with significant morbidity and mortality. The clinical management of such diseases involves several strategies, being one of those the inhibition of key enzymes involved in androgen biosynthesis, such as 5α-reductase and the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17) (Scheme 1) [4]. The most common of these two prostatic diseases is BHP, whose incidence rates escalate rapidly with age, with the majority of men being affected at age 80 [5], [6]. This disease is a non-cancerous growth of the prostate involving the over proliferation of stromal and epithelial glandular elements of the prostate [7], leading mainly to lower urinary tract symptoms (LUTS). In fact, in BPH an obstruction of the urethra and the gradual loss of bladder function are observed, resulting in incomplete bladder emptying. Accordingly, the typical symptoms of BPH, which can significantly compromise the quality of life, are generally obstructive (e.g., poor urine stream and large residual urine volume) and irritative (e.g., hesitancy and increased frequency of urination). The enlarging prostate increases the adrenergic tone of this gland in patients, resulting in further tightening of the urethra.