Discovery of pyrrolopyridazines as novel DGAT1 inhibitors.
A new structural class of DGAT1 inhibitors was discovered and the structure-activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC(50) values ranging from >10 μM to 48 nM.
Fox
Brian M
BM
Amgen Inc., Amgen South San Francisco, South San Francisco, CA 94080, USA.
Iio
Kiyosei
K
Li
Kexue
K
Choi
Rebeka
R
Inaba
Takashi
T
Jackson
Simon
S
Sagawa
Shoichi
S
Shan
Bei
B
Tanaka
Masahiro
M
Yoshida
Atsuhito
A
Kayser
Frank
F
D002460:Cell Line; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011724:Pyridazines; D011758:Pyrroles; C508945:Pyrrolopyridazine; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1