A new generation of progesterone receptor modulators.
Progesterone receptor (PR) modulators have evolved both structurally and mechanistically over the past half-century. Classical steroidal PR agonists continue to play an important role in women's health such as in oral contraception and post-menopausal hormone therapy whereas steroid-based PR antagonists and selective PR modulators are being evaluated clinically in a wide range of gynecologic conditions. This review will focus primarily on the newer generation of PR modulators derived from structurally unique chemical scaffolds. For example, tanaproget (TNPR) is described as a non-steroidal PR agonist with high affinity and selectivity for the PR that is significantly more potent than many of its steroidal counterparts in a variety of pre-clinical efficacy models. Similarly, we present numerous examples of unique non-steroidal PR antagonists in various stages of characterization and development. A basic understanding of the structural determinants for high affinity binding of these new PR modulators to the PR ligand-binding domain (LBD) is also discussed. Finally, as the biology of the PR becomes further defined, we speculate on the future development of novel PR modulators.
Winneker
Richard C
RC
Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, PA 19426, USA. WinnekR@wyeth.com
Fensome
Andrew
A
Zhang
Puwen
P
Yudt
Matthew R
MR
McComas
Casey C
CC
Unwalla
Rayomond J
RJ
D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology; D004963:Estrenes / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006067:Gonanes / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology; D011374:Progesterone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology
D048588:Benzoxazines; D004963:Estrenes; D006067:Gonanes; D007211:Indoles; D010091:Oximes; D020033:Protein Isoforms; D011980:Receptors, Progesterone; D013871:Thiones; D011374:Progesterone; C488516:asoprisnil; C053238:onapristone; C504446:tanaproget