Discovery of orally active, pyrrolidinone-based progesterone receptor partial agonists.
We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivity against hERG channel inhibition.
Washburn
David G
DG
Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA. dave.g.washburn@gsk.com
Hoang
Tram H
TH
Frazee
James S
JS
Johnson
Latisha
L
Hammond
Marlys
M
Manns
Sharada
S
Madauss
Kevin P
KP
Williams
Shawn P
SP
Duraiswami
Chaya
C
Tran
Thuy B
TB
Stewart
Eugene L
EL
Grygielko
Eugene T
ET
Glace
Lindsay E
LE
Trizna
Walter
W
Nagilla
Rakesh
R
Bray
Jeffrey D
JD
Thompson
Scott K
SK
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D011760:Pyrrolidinones; D011980:Receptors, Progesterone