3-heptylamino-5-phenylpyridazine derivatives as analogues of Acyl-CoA: cholesterol acyltransferase inhibitors containing the N-heptyl-N'-arylureidic moiety.
A series of novel Acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors 8a-f was synthesized; the substances were characterized by the presence of a 2,5-dimethylpyrazin-3-yl moiety at one end and a 3-heptylamino-5-phenylpyridazine system at the other one, linked through linear alkyl spacers of different length. The new derivatives were designed based on the hypothesis that the 3-amino-5-phenylpyridazine moiety could mimic the aryl substituted urea, which was present in a number of ACAT inhibitors previously described. The choice of the 2,5-dimethylpyrazin-3-yl substituent was supported by a preliminary investigation, which indicated that this moiety is the most powerful in conferring ACAT inhibitory properties to the new series. The pharmacological results proved the idea to be sound. Finally, compounds 9a-c, lacking the phenylpyridazine moiety were prepared and tested to further strengthen our hypothesis.
Gelain
Arianna
A
Istituto di Chimica Farmaceutica e Tossicologica, Università di Milano, Viale Abruzzi 42, I-20131 Milan, Italy.
Barlocco
Daniela
D
Kwon
Byong-Mog
BM
Jeong
Tae-Sook
TS
Im
Kyung-Ran
KR
Legnani
Laura
L
Toma
Lucio
L
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000201:enzymology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D011724:Pyridazines; D002785:Sterol O-Acyltransferase