Castoria- Varchi 2012 (original) (raw)
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Nonsteroidal Androgen Receptor Ligands: Versatile Syntheses and Biological Data
ACS Medicinal Chemistry Letters, 2012
We report herein a stereoselective and straightforward methodology for the synthesis of new androgen receptor ligands with (anti)-agonistic activities. Oxygenânitrogen replacement in bicalutamide-like structures paves the way to the disclosure of a new class of analogues, including cyclized/nitrogen-substituted derivatives, with promising antiandrogen (or anabolic) activity.
European Journal of Medicinal Chemistry, 2002
While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R 2 position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, 3 H-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy.
Endocrinology, 2005
We recently reported two nonsteroidal androgen receptor (AR) ligands that demonstrate tissueselective pharmacological activity, identifying these S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4nitro-3-trifluoromethyl-phenyl)-propionamide analogs as the first members of a new class of drugs known as selective androgen receptor modulators. The purpose of these studies was to explore additional structure-activity relationships of selective androgen receptor modulators to enhance their AR binding affinity, AR-mediated transcriptional activation, and in vivo pharmacological activity. The AR binding affinity (K i ) of 29 novel synthetic AR ligands was determined by a radioligand competitive binding assay and ranged from 1.0-51 nM. Compounds with electron-withdrawing substituents at the para-and meta-positions of the B-ring demonstrated the highest AR binding affinity. The AR-mediated transcriptional activation was determined using a cotransfection assay in CV-1 cells. Most compounds with two substituents in the B-ring maintained or improved their functional activity in vitro. However, compounds with three halogen substituents exhibited significant regioselectivity. Fifteen compounds were selected to examine their pharmacological activity in castrated rats. In vivo pharmacological activity and selectivity were significantly changed by structural modification in the B-ring. Compounds with halogen groups at the para-and metapositions of the B-ring displayed the highest pharmacological activity. Incorporating substituents at the ortho-position of the B-ring resulted in poor pharmacological activity. In vitro and in vivo agonist activities were partially correlated. In conclusion, novel selective androgen receptor modulators with improved in vivo pharmacological activity can be designed and synthesized based on the structureactivity relationship identified in these studies.
Journal of Medicinal Chemistry, 2014
The androgen receptor (AR) represents the primary target for prostate cancer (PC) treatment even when the disease progresses toward androgen-independent (AIPC) or castration-resistant (CRPC) forms. Because small chemical changes in the structure of nonsteroidal AR ligands determine the pharmacological responses of AR, we developed a novel stereoselective synthetic strategy that allows sterically hindered C2-substituted bicalutamide analogues to be obtained. Biological and theoretical evaluations demonstrate that C2substitution with benzyl and phenyl moieties is a new, valuable option toward improving pan-antagonist behavior. Among the synthesized compounds, (R)-16m, when compared to casodex, (R)-bicalutamide, and enzalutamide, displayed very promising in vitro activity toward five different prostate cancer cell lines, all representative of CPRC and AIPC typical mutations. Despite being less active than (R)-bicalutamide, (R)-16m also displayed marked in vivo antitumor activity on VCaP xenografts and thus it may serve as starting point for developing novel AR panantagonists.
Discovery and biological characterization of a novel series of androgen receptor modulators
2009
Background and purpose: Selective androgen receptor modulators are of great value in the treatment of prostate cancer. The purpose of this study was to provide a preliminary characterization of a new class of non-steroidal androgen receptor modulators discovered in a high-throughput screening campaign. Experimental approach: Competitive receptor binding, luciferase-based reporter methods, cell proliferation and in vivo assays were employed to evaluate an initial set of compounds from chemistry efforts. Key results: Forty-nine analogues from the chemistry efforts showed high affinity binding to androgen receptors, agonist and/ or antagonist activities in both CV-1 and MDA-MB-453 transfection assays. A proliferation assay in LNCaP cells also exhibited this profile. A representative of these non-steroidal compounds (compound 21) was devoid of activity at other nuclear receptors (oestrogen, progesterone, glucocorticoid and mineralocorticoid receptors) in the CV-1 co-transfection assay. At the same time, in an immature castrated rat model, it behaved as an androgen receptor antagonist against the growth of prostate, seminal vesicles and levator ani induced by exogenous androgen. Separation of compound 21 into its enantiomers showed that nearly all the androgen receptor modulating activity and binding resided in the dextrorotatory compound (23) while the laevorotatory isomer (22) possessed weak or little effect depending on the cell type studied. Conclusions and implications: These non-steroidal compounds may represent a new class of androgen receptor modulators for the treatment of not only prostate cancer but other clinical conditions where androgens and androgen receptors are involved in the pathological processes.
Key Structural Features of Nonsteroidal Ligands for Binding and Activation of the Androgen Receptor
Molecular Pharmacology, 2003
The purposes of the present studies were to examine the androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of highaffinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective androgen receptor modulators (SARMs) for androgen therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.
Journal of medicinal chemistry, 2004
A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgen receptor (AR). These ligands were designed to eliminate metabolic sites identified in one of our first-generation AR agonists, which was inactive in vivo due to its rapid metabolism to inactive constituents. The binding affinity of these compounds was evaluated using AR isolated from rat ventral prostate. These second-generation compounds bound the AR in a high affinity and stereoselective manner, with K(i) values ranging from about 4 to 130 nM. The ability of these ligands to stimulate AR-mediated transcriptional activation was examined in cells transfected with the human AR and a hormone-dependent luciferase reporter gene. Although some compounds were unable to stimulate AR-mediated transcription, several demonstrated activity similar to that of dihydrotestosterone (DHT, an endogenous steroidal ligand for the AR). We also evaluated the in vivo pharmacologic activity of selected compoun...