Novel 3‐Arylamino‐ and 3‐Cycloalkylamino‐5,6‐diphenyl‐pyridazines Active as ACAT Inhibitors.

Abstract

A new series of pyridazine derivatives, structurally related to the previously reported ACAT inhibitors 3-(cyclo)alkylamino-5,6-diphenyl-pyridazines, were synthesized and tested for their inhibitory properties. Substitution of the 3-alkylamino chain with a phenylamino group maintains activity. In contrast, the presence of either substituents on the phenylamino group or aliphatic rings having more or less than six carbon atoms lowers it.

Mono- or Diphenylpyridazines Connected to N-(2,4-Difluorophenyl)-N‘-heptylurea as Acyl-CoA:Cholesterol Acyltransferase Inhibitors

“…8 To better define the structural requirements of this class, a series of derivatives with different substituents both on the o-diphenyl system and the side-chain were also synthesized. [9][10][11] As a part of our ongoing research program, we describe herein the design, the synthetic approach, the results of the enzyme assay, and the conformational study for novel series of compounds (1)(2)(3)(4), structurally related to DuP 128, a potent ureido derivative, which antagonizes ACAT from rat hepatic microsomes with an IC 50 ) 10 nM (Chart 1). 12 Compounds 1-4 combine the characteristic substituted urea of DuP 128 with pyridazine, which serves as the central ring template.…”

Discovery of Novel Acyl Coenzyme A: Cholesterol Acyltransferase Inhibitors: Pharmacophore‐Based Virtual Screening, Synthesis and Pharmacology

“…For the pharmacophore modeling studies, a set of 46 ACAT inhibitors were selected from the literature (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and divided into a training set (21 molecules, Chart S1) and a test set (25 molecules, Chart S2) based on principles of structural diversity and wide coverage of the activity range (between 0.002 and 230 lM, six orders of magnitude). Structures of all compounds in this study were sketched using the Visualizer module of Discovery Studio 2.1.…”

Biphenyl versus Phenylpyridazine Derivatives: The Role of the Heterocycle in a Series of Acyl-CoA:Cholesterol Acyl Transferase Inhibitors

“…Although the pyridazine derivatives were less potent than the imidazolyl model, they retained interesting properties. To verify the importance of different parameters, subsequent SAR studies were carried out in our laboratories both on the alkyl side chain and on the two phenyl groups in positions meta and para with respect to it. – Beside giving information on several structural requirements for the optimum activity of these compounds, evidence was provided that in our series the two adjacent phenyl groups were not essential and only one of them was required on the pyridazine ring. In addition, in all of the compounds we prepared, the best results were obtained when the linker between the aryl moiety and the side chain was a secondary amino group ( I , X = NH.…”