Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines.
Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.
Kaizerman
Jacob A
JA
Amgen, Inc., South San Francisco, CA 94080, USA.
Aaron
Wade
W
An
Songzhu
S
Austin
Richard
R
Brown
Matt
M
Chong
Angela
A
Huang
Tom
T
Hungate
Randall
R
Jiang
Ben
B
Johnson
Michael G
MG
Lee
Gary
G
Lucas
Brian S
BS
Orf
Jessica
J
Rong
Minqing
M
Toteva
Maria M
MM
Wickramasinghe
Dineli
D
Xu
Guifen
G
Ye
Qiuping
Q
Zhong
Wendy
W
McMinn
Dustin L
DL
D000818:Animals; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000077297:Pregnane X Receptor; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D011987:Receptors, Steroid / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship; D015645:Tylosin / Q000031:analogs & derivatives
C114856:4-'demycarosyl-20-deoxo-20-(di-N-benzylamino)-8a-aza-8a-homotylosin; C553441:4-(4-phenylphthalazine-1-yl)piperazine amide; D053823:Hedgehog Proteins; D010793:Phthalazines; D010879:Piperazines; D000077297:Pregnane X Receptor; D011724:Pyridazines; D043562:Receptors, G-Protein-Coupled; D011987:Receptors, Steroid; C491023:SMO protein, human; D000072086:Smoothened Receptor; C062482:pyridazine; C043388:phthalazine; D015645:Tylosin