Discovery of novel hydroxy-thiazoles as HIF-alpha prolyl hydroxylase inhibitors: SAR, synthesis, and modeling evaluation.
Inhibition of the PHD2 enzyme has been associated with increased red blood cell levels. From a screening hit, a series of novel hydroxyl-thiazoles were developed as potent PHD2 inhibitors.
Tegley
Christopher M
CM
Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. ctegley@amgen.com
Viswanadhan
Vellarkad N
VN
Biswas
Kaustav
K
Frohn
Michael J
MJ
Peterkin
Tanya A N
TA
Chang
Catherine
C
Bürli
Roland W
RW
Dao
Jennifer H
JH
Veith
Henrike
H
Rogers
Norma
N
Yoder
Sean C
SC
Biddlecome
Gloria
G
Tagari
Philip
P
Allen
Jennifer R
JR
Hungate
Randall W
RW
D002626:Chemistry, Pharmaceutical / Q000379:methods; D003920:Diabetes Mellitus / Q000188:drug therapy; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000138:chemical synthesis* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D009203:Myocardial Infarction / Q000188:drug therapy; D016491:Peripheral Vascular Diseases / Q000628:therapy; D020521:Stroke / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013844:Thiazoles