Selective progesterone receptor antagonists for the treatment of endometriosis

ORGN 661

Kevin N. Dack, kevin.dack@pfizer.com, Patrick S Johnson, Paul A Bradley, Sarah Skerratt, Ian R Marsh, and Toby Underwood. Sandwich Chemistry, Pfizer Global Research & Development, Sandwich, United Kingdom
Endometriosis is a common gynaecological disease that affects ~10-20% of women of reproductive age and manifests as lesions outside of the uterine cavity. Common symptoms include dysmenorrhea, infertility, and chronic pelvic and abdominal pain. At its most severe, endometriosis can cause profound structural modification of the peritoneal cavity, including multi-organ adhesions and fibrosis. Surgical intervention can be moderate or severe, with substantial numbers of patients undergoing hysterectomy. Progression of endometriosis is generally accepted to be under the influence of the estrogen/progesterone cycle, and modulation of these steroidal pathways may have utility in treating this condition. We reasoned that selective antagonists of the progesterone (PR) receptor, a member of the steroid-activated nuclear hormone receptor family, could provide good efficacy coupled with a benign side effect profile. The presentation will cover highlights of the synthesis and SAR of a series of selective cyanophenoxy-heterocycle based PR antagonists.