Mono- or diphenylpyridazines connected to N-(2,4-difluorophenyl)-N'-heptylurea as acyl-CoA:cholesterol acyltransferase inhibitors.
Mono- and diphenylpyridazine ureido derivatives, structurally related to DuP 128, were synthesized and tested for their inhibitory activity against ACAT isolated from rat liver microsomes. Several compounds displayed ACAT inhibition in the micromolar range. The amino derivatives 4a-c were also tested against hACAT-1 and hACAT-2 isoforms. They retained the same trend shown in the previous assay. Modeling studies on representative terms were performed. Significant similarities between the geometrical features of the model DuP 128 and the most active pyridazine derivatives were observed.
Gelain
Arianna
A
Istituto di Chimica Farmaceutica e Tossicologica, Università di Milano, Viale Abruzzi 42, 20131 Milano, Italy. daniela.barlocco@unimi.it
Bettinelli
Ilaria
I
Barlocco
Daniela
D
Kwon
Byoung-Mog
BM
Jeong
Tae-Sook
TS
Cho
Kyung-Hyun
KH
Toma
Lucio
L
D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology; D008958:Models, Molecular; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D000097587:Sterol O-Acyltransferase 2
D000101:Acetyl-CoA C-Acetyltransferase; D010671:Phenylurea Compounds; D020033:Protein Isoforms; D011724:Pyridazines; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C506639:ACAT1 protein, human