pubs.acs.org/jmc Published on Web 12/03/2010 r 2010 American Chemical Society 302 J. Med. Chem. 2011, 54, 302–311 DOI: 10.1021/jm101163m Arylpiperazines for Management of Benign Prostatic Hyperplasia: Design, Synthesis, Quantitative Structure-Activity Relationships, and Pharmacokinetic Studies † Amit Sarswat, ‡ Rajeev Kumar, § Lalit Kumar, ‡ Nand Lal, ‡ Smriti Sharma, ‡ Yenamandra S. Prabhakar, ‡ Shailendra K. Pandey, ) Jawahar Lal, ) Vikas Verma, § Ashish Jain, § Jagdamba P. Maikhuri, § Diwakar Dalela, ^ Kirti, ^ Gopal Gupta, § and Vishnu L. Sharma* ,‡ ‡ Medicinal & Process Chemistry Division, § Endocrinology Division, and ) Pharmacokinetics & Metabolism Division, Central Drug Research Institute (CSIR), Lucknow-226001, India, and ^ Department of Urology, CSM Medical University, Lucknow-226001, India Received September 8, 2010 A series of 27 aryl/heteroaryl/aralkyl/aroyl piperazines were synthesized, and most of these compounds reduced prostate weight of mature rats by 15-47%. Three compounds, 10, 12, and 18, had better activity profile (reduced prostate weight by 47%, 43%, and 39%, respectively) than the standard drug flutamide (24% reduction). QSAR suggested structures with more cyclic and branched moieties, increased topological separation of O and N therein, and reduced solvation connectivity index for better activity. Pharmacokinetic study with compound 10 at an oral dose of 10.0 mg/kg indicated good absorption, negligible extrahepatic elimination, and rapid distribution to the target organ (prostate) but restricted entry through the blood-brain barrier. A 10-fold decrease in PSA and 15-fold increase in ER- β gene expressions of human prostate cancer cells (LNCaP) by compound 10 in vitro indicated AR and ER-β mediated actions. The findings may stimulate further explorations of identified lead for the management of benign prostatic hyperplasia. Introduction Benign prostatic hyperplasia (BPH) a is an ubiquitous 1 con- dition in aging males, such that the incidence of BPH detected at autopsy increases from approximately 30% at age 50 to >80% at age 80. Unfortunately, the urinary symptoms attributed to BPH lead to significant erosion in the quality of life for affected men. 2 The available treatments for BPH are either highly invasive (surgical) or partially effective with unwanted side effects and put a significant burden on employees and their employers through direct medical costs and lost work time. Direct and indirect private sector costs related to BPH treatment are an estimated $3.9 billion. 3 It is well established that andro- gens, such as testosterone and 5R-dihydrotestosterone (DHT), play an essential role in stimulating hyperplasia and carcinoma of hormone-sensitive tissue such as that of the prostate. 4 The two medical treatments currently used for BPH are R-adrenergic blockers (e.g., terazosin, tamsulosin) and 5R-reductase inhibi- tors (e.g., finasteride). While the former are more effective in relieving BPH symptoms, 5 only the latter reduce prostate volume and hence the risk of acute urinary retention. 6 Potential cardiovascular consequences and sexual dysfunction are the major issues associated with therapies involving R-adrenergic blockers and 5R-reductase inhibitors, respectively. Tamsulosin has fewer cardiovascular side effects due to its selectivity for R 1a - adrenergic receptors which are concentrated mainly in the prostate but may cause floppy iris syndrome and sulfa drug- type adverse effects. 7 Steroidal AR antagonists, such as cyproterone acetate 8 (Figure 1), block androgen action and also have progestational and glucocorticoid activities. Their overlapping effects with other hormonal systems cause a range of unpleasant side effects including thrombosis, fluid retention, and loss of libido, which hinder their use as agents for management of BPH. 9 A number of nonsteroidal AR antagonists, including flutamide 10-12 (Figure 1), nilutamide 13 (Figure 1), and bicalutamide 14-18 (Figure 1), have been reported in the literature. 19-29 Nonsteroidal AR antagonists selectively block androgen action without affecting other hormonal systems, and side effects such as loss of libido and impotence are therefore less profound. However, they do inhibit the binding of testoster- one to ARs in the central nervous system (CNS) which, in turn, interrupts the negative feedback of testosterone on gonadotropin secretion, causing an increased serum testoster- one level. 30 This increase in serum testosterone impairs the antiandrogenic activity of AR antagonists and also causes side effects including gynecomastia and breast tenderness. There- fore, potent AR antagonists with fewer adverse effects are highly desirable. Recently, arylpiperazine derivatives have been reported as potent nonsteroidal AR antagonists, 31,32 and some of them † CDRI Communication No. 7892. *To whom correspondence should be addressed. Phone: 91-522- 2612411 ext 4320. Fax: 91-522-2623405. E-mail: vlscdri1@rediffmail. com; vlscdri@gmail.com. a Abbreviations: BPH, benign prostatic hyperplasia; QSAR, quanti- tative structure-activity relationship; PSA, prostate-specific antigen; ER, estrogen receptor; AR, androgen receptor; DHT, 5R-dihydrotes- tosterone; SARMs, selective androgen receptor modulators; PCR, polymerase chain reaction; MRT, mean residence time; BR, biological response; CP-MLR, combinatorial protocol in multiple linear regres- sion; LOO, leave-one-out; SPI, superpendentic index; TEA, triethyla- mine; DCM, dichloromethane; TURP, trans-urethral resection of prostate; FCS, fetal calf serum; dNTP, deoxyribonucleoside tripho- sphate; HPLC, high-performance liquid chromatography.