N-Arylpiperazine-1-carboxamide Derivatives: a Novel Series of Orally Active Nonsteroidal Androgen Receptor Antagonists

Abstract

Prostate cancer has become the most common cancer among men, and the second leading cause of male cancer deaths in the United States.1) Testosterone and 5a-dihydrotestosterone are androgens that are required for the development of both the normal prostate and prostate cancer. 2)Androgens act through the androgen receptor (AR), which belongs to the steroid-receptor superfamily of ligand-dependent transcription factors.3,4) Both steroidal and nonsteroidal antiandrogens are available, and these molecules are of clinical utility as chemotherapeutic agents for prostate cancer (Fig. 1). 5,6) Cyproterone acetate (CPA: 1) is a typical steroidal AR antagonist.7) It was one of the earliest of these drugs to be administered orally, but CPA shows agonistic activity and overlapping effects with other hormonal systems, leading to a range of unpleasant side effects. A number of nonsteroidal AR antagonists have been reported in the literature [8][9][10][11][12][13][14][15][16][17] and three of these, flutamide (2), [18][19][20] nilutamide (3) 21) and bicalutamide (4) [22][23][24][25] (Fig. 1), are pure antiandrogens used in the treatment of prostate cancer. 26) However, these nonsteroidal AR antagonists exhibit adverse effects such as mastodynia, gynaecomastia and hepatotoxicity [18][19][20][21][22][23][24][25] ; and therefore potent AR antagonists with fewer adverse effects are highly desirable. Moreover, flutamide therapy requires administration three times each day, and bicalutamide is taken once a day. Therefore, from a quality of life perspective, it would be desirable for new generation AR antagonists to have a longer duration of action, at least equal to that of bicalutamide.In a previous paper, 27) we reported a new series of N-arylpiperazine derivatives as potent nonsteroidal AR antagonists. Among these derivatives, YM-92088 (5) was shown to be a more potent than bicalutamide as an in vitro AR antagonist (4). However, the in vivo antiandrogenic activity of 5 was lower than that of bicalutamide. Hence, to find AR antagonists with greater oral potency, we have conducted further modification of 5, and in this paper we describe the results of our studies on the synthesis and pharmacological evaluation of a series of N-arylpiperazine-1-carboxamide derivatives as AR antagonists. ChemistryCompounds selected for biological evaluation were prepared as described in Charts 1-4. All synthesized compounds were characterized by 1 H-NMR, mass spectrometry and elemental analysis.As shown in Chart 1, compounds 7-12 and 19 were prepared in good yields by ipso substitution of 4-fluoro-2-(trifluoromethyl)benzonitrile (6) with the corresponding cyclic amines and, in the case of compound 9, by subsequent deprotection of the Boc group. Treatment of 7-12 with 4-fluorophenyl isocyanate afforded the urea derivatives 13-18a. The amide derivative (20) was obtained from compound 19 by hydrolysis followed by conventional amidation. Compound 22 was obtained by coupling N-Boc piperidinone with 4-bromo-2-(trifluoromethyl)benzonitrile, which was prepar...

Androgen Receptor Antagonists and Anti-Prostate Cancer Activities of Some Newly Synthesized Substituted Fused Pyrazolo-, Triazolo- and Thiazolo-Pyrimidine Derivatives

“…The stable transfected cells were selected in the culture medium supplemented with neomycin. The selected clone was designated as AR/CHO#3 (human AR gene and MMTV luciferase reporter gene integrated CHO cell) or SV/CHO#10 (SV-40-luciferase reporter gene integrated CHO cell), respectively [31]. …”

“…The rats were sacrificed by excessive chloroform anesthesia 6 h after final dosing, and both their ventral prostates and seminal vesicles-coagulate glands were removed and weighed. The anti-androgenic activity was expressed as a percentage of inhibition of the TP effect (TP-treated rats were arbitrarily assigned a value of 0% and vehicle-treated rats a value of 100%) [31]. …”

Androgen Receptor Antagonists and Anti-prostate Cancer Activities of Some Synthesized Steroidal Candidates

“…In Vivo Evaluation of Antiandrogenic Activities in Castrated Immature Rats 22) Andorgen treated male Wistar rats were obtained from the Animal House Colony, Research Institute of Ophthalmology, Giza, Egypt. Prepubertal male rats aged 3 weeks were castrated by the scrotal route under ether anesthesia.…”

Developments in Nonsteroidal Antiandrogens Targeting the Androgen Receptor

“…The derivative YM92088 ( 51 ; IC 50 =0.47 μ M ) exhibited greater potency as an in vitro AR antagonist than R ‐bicalutamide ( 2 ; IC 50 =0.89 μ M ). However, the in vivo activity was lower than that of R ‐bicalutamide ( 2 )—32 % and 75 % inhibition, respectively, and 51 was found to be metabolically unstable in human liver microsomes 42. A series of N ‐arylpiperazine‐1‐carboxamide derivatives of 51 (YM92088) were synthesized (compounds 52 – 55 );42 these modifications improved the inhibitory activity, the metabolic stability profile and the oral potency.…”

“…However, the in vivo activity was lower than that of R ‐bicalutamide ( 2 )—32 % and 75 % inhibition, respectively, and 51 was found to be metabolically unstable in human liver microsomes 42. A series of N ‐arylpiperazine‐1‐carboxamide derivatives of 51 (YM92088) were synthesized (compounds 52 – 55 );42 these modifications improved the inhibitory activity, the metabolic stability profile and the oral potency. The biological data demonstrated that other alternative cyclic amines and ring expansion of the piperazine are unfavorable for AR antagonism.…”