Improving the developability profile of pyrrolidine progesterone receptor partial agonists.
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
Kallander
Lara S
LS
Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. lara.s.kallander@gsk.com
Washburn
David G
DG
Hoang
Tram H
TH
Frazee
James S
JS
Stoy
Patrick
P
Johnson
Latisha
L
Lu
Qing
Q
Hammond
Marlys
M
Barton
Linda S
LS
Patterson
Jaclyn R
JR
Azzarano
Leonard M
LM
Nagilla
Rakesh
R
Madauss
Kevin P
KP
Williams
Shawn P
SP
Stewart
Eugene L
EL
Duraiswami
Chaya
C
Grygielko
Eugene T
ET
Xu
Xiaoping
X
Laping
Nicholas J
NJ
Bray
Jeffrey D
JD
Thompson
Scott K
SK
D000818:Animals; D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry; D018360:Crystallography, X-Ray; D000072237:ERG1 Potassium Channel; D004715:Endometriosis / Q000188:drug therapy; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005260:Female; D006801:Humans; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry
D002219:Carbamates; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011759:Pyrrolidines; D011980:Receptors, Progesterone; D013449:Sulfonamides; C032519:pyrrolidine