Synthesis and structure-activity relationship of novel 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones as progesterone receptor modulators leading to the potent and selective nonsteroidal progesterone receptor agonist tanaproget.
Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.
Fensome
Andrew
A
Chemical and Screening Sciences, Women's Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. fensoma@wyeth.com
Bender
Reinhold
R
Chopra
Rajiv
R
Cohen
Jeff
J
Collins
Mark A
MA
Hudak
Valerie
V
Malakian
Karl
K
Lockhead
Susan
S
Olland
Andrea
A
Svenson
Kristine
K
Terefenko
Eugene A
EA
Unwalla
Ray J
RJ
Wilhelm
James M
JM
Wolfrom
Scott
S
Zhu
Yuan
Y
Zhang
Zhiming
Z
Zhang
Puwen
P
Winneker
Richard C
RC
Wrobel
Jay
J
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D003271:Contraceptive Agents, Female / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003656:Decidua / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D015394:Molecular Structure; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D048588:Benzoxazines; D003271:Contraceptive Agents, Female; D008024:Ligands; D010078:Oxazines; D011758:Pyrroles; D011980:Receptors, Progesterone; D013871:Thiones; C503890:tanoproget; D000469:Alkaline Phosphatase