Discovery of pyrrolopyridazines as novel DGAT1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2010-10, Vol.20 (20), p.6030-6033
• Main Authors: Fox, Brian M., Iio, Kiyosei, Li, Kexue, Choi, Rebeka, Inaba, Takashi, Jackson, Simon, Sagawa, Shoichi, Shan, Bei, Tanaka, Masahiro, Yoshida, Atsuhito, Kayser, Frank
• Format: Article
• Language: English
• Subjects: Acyl CoA:diacylglycerol acyltransferase; Biological and medical sciences; Cell Line; DGAT1; DGAT1 inhibitors; Diacylglycerol O-Acyltransferase - antagonists & inhibitors; Diacylglycerol O-Acyltransferase - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Humans; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrrolopyridazines; Sterol O-Acyltransferase - antagonists & inhibitors; Sterol O-Acyltransferase - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.08.066

A new structural class of DGAT1 inhibitors possessing a pyrrolopyridazine core has been discovered. The optimization of DGAT1 inhibitory activity and increase in selectivity over ACAT1 is described. 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.