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

doi:10.1016/j.bmcl.2011.11.068

Discovery of 3-aryloxy-lactam analogs as potent androgen receptor full antagonists for treating castration resistant prostate cancer

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1230-6. doi: 10.1016/j.bmcl.2011.11.068. Epub 2011 Dec 9.

Authors

Chuangxing Guo¹, Susan Kephart, Martha Ornelas, Javier Gonzalez, Angelica Linton, Mason Pairish, Asako Nagata, Samantha Greasley, Jeff Elleraas, Natilie Hosea, Jon Engebretsen, Andrea N Fanjul

Affiliation

¹ Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA. [email protected]

PMID: 22197140
DOI: 10.1016/j.bmcl.2011.11.068

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. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
High-Throughput Screening Assays
Humans
Lactams / chemical synthesis
Lactams / chemistry
Lactams / pharmacology*
Male
Models, Molecular
Molecular Structure
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / surgery
Receptors, Androgen / chemistry*
Receptors, Androgen / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

Lactams
Receptors, Androgen