Discovery of pyrrolopyridazines as novel DGAT1 inhibitors

Brian M Fox; Kiyosei Iio; Kexue Li; Rebeka Choi; Takashi Inaba; Simon Jackson; Shoichi Sagawa; Bei Shan; Masahiro Tanaka; Atsuhito Yoshida; Frank Kayser

doi:10.1016/j.bmcl.2010.08.066

Discovery of pyrrolopyridazines as novel DGAT1 inhibitors

Bioorg Med Chem Lett. 2010 Oct 15;20(20):6030-3. doi: 10.1016/j.bmcl.2010.08.066. Epub 2010 Aug 18.

Authors

Brian M Fox¹, Kiyosei Iio, Kexue Li, Rebeka Choi, Takashi Inaba, Simon Jackson, Shoichi Sagawa, Bei Shan, Masahiro Tanaka, Atsuhito Yoshida, Frank Kayser

Affiliation

¹ Amgen Inc., Amgen South San Francisco, South San Francisco, CA 94080, USA.

PMID: 20833038
DOI: 10.1016/j.bmcl.2010.08.066

Abstract

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.

MeSH terms

Cell Line
Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
Diacylglycerol O-Acyltransferase / metabolism*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Humans
Inhibitory Concentration 50
Pyridazines / chemical synthesis
Pyridazines / chemistry*
Pyridazines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry*
Pyrroles / pharmacology*
Sterol O-Acyltransferase / antagonists & inhibitors
Sterol O-Acyltransferase / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Pyridazines
Pyrroles
Pyrrolopyridazine
DGAT1 protein, human
Diacylglycerol O-Acyltransferase
Sterol O-Acyltransferase
sterol O-acyltransferase 1