Discovery of 3-aryloxy-lactam analogs as potent androgen receptor full antagonists for treating castration resistant prostate cancer Chuangxing Guo ⇑ , Susan Kephart ⇑ , Martha Ornelas, Javier Gonzalez, Angelica Linton, Mason Pairish, Asako Nagata, Samantha Greasley, Jeff Elleraas, Natilie Hosea, Jon Engebretsen, Andrea N. Fanjul Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA article info Article history: Received 13 October 2011 Revised 14 November 2011 Accepted 18 November 2011 Available online 9 December 2011 Keywords: Androgen receptor AR antagonist Prostate cancer Ligand efficiency Polar surface area PSA Castration resistant prostate cancer CRPC LBD NHR abstract High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improve- ments in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities. Ó 2011 Elsevier Ltd. All rights reserved. Several androgen receptor (AR) antagonists have been investi- gated in clinical trials against prostate cancer. 1 One example is bicalutamide (Casodex Ò , Fig. 1), which is used along with chemical or surgical castration in the combined androgen blockade (CAB) protocol for prostate cancer treatment. 2 Unfortunately, bicaluta- mide (alone or in combination therapy) loses efficacy after only a few months to a few years of treatment. Oncogenic mutations or changes in gene expression make the cancer cells resistant to hor- mone blockade, resulting in castration-resistant prostate cancer (CRPC), also known as hormone refractory prostate cancer (HRPC). Elevated AR expression in tumor cells correlates with a change in the functional activity of bicalutamide from antagonist to agonist, 3 suggesting that prostate tumors may adapt to survive on any resid- ual agonism a drug molecule may induce. This antagonist-to-ago- nist switch has also been observed for other drugs, 3 and may be responsible for drug resistance in CRPC patients. Recently, novel AR antagonists such as MDV-3100 and BMS-641988 (Fig. 1) have demonstrated efficacy against CPRC in preclinical models, 4,5 and more importantly, in patients. 6 These results encouraged our own search for novel, non-steroidal, pure antagonists of AR in CRPC cells. Pfizer has a collection of AR antagonists synthesized for an ear- lier program targeting topical treatments for hair-loss and excess sebum production. 7 These compounds were screened for AR antag- onism in a high-throughput assay based on CRPC cells, 8 and 1 (Fig. 2) was identified as a potent antagonist (AR antagonism IC 50 = 77 nM). Initial follow-up chemistry efforts on close-in ana- logs revealed that, after chiral resolution, the more potent diaste- reomers (e.g., 2) are partial AR antagonists with significant residual agonism, 9 but removal of the methyl group (e.g., 3) elim- inated AR agonism. These leads were profiled for their ADME prop- erties and were found to have good permeability (data not shown), but suffered from generally high unbound clearance in vitro (HLM unbound Clint 10 19.3–115 lL/min/mg) and in vivo (unbound Cl: 11 921–1585 mL/min/kg in rat) as well as low solubility (<10 lg/mL at pH 7.4). Both of these factors are likely to be underlying causes of low oral absorption (Fa <25%) observed in rat PK studies of these leads. Since an orally active agent was our goal, we sought to improve solubility and reduce unbound clearance. Both problems may be due to the high lipophilicity (c Log P) of these molecules. Our strat- egy was to reduce lipophilicity by modifying either the substituent on the lactam nitrogen (right-hand side) or the aryl ether (left- hand side), in such a way that would maintain the full antagonist profile. Analysis of the existing SAR on this series revealed that 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.11.068 ⇑ Corresponding authors. E-mail address: alex.guo@pfizer.com (C. Guo). Bioorganic & Medicinal Chemistry Letters 22 (2012) 1230–1236 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl