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

Abstract

A series of alkylamido- ( 1) and alkylaminobiphenyl ( 2) derivatives were synthesized as possible bioisosters of the reported ACAT inhibitors phenylpyridazine analogues ( I). Both 1 and 2 were tested on the human ACAT-1 and ACAT-2 isoforms. The amino derivatives 2 were found to be inactive, contrary to the related pyridazine derivatives. By contrast, the ortho -substituted amides 1a and 1d showed an interesting activity. These results support the essential role of the pyridazine nucleus. Modeling studies were also performed.

Synthesis of Some New Pyridazine Derivatives for Anti-HAV Evaluation

“…Pyridazine-based frameworks are widely distributed in biologically active products with anti-viral [ 15 , 16 , 17 , 18 , 19 , 20 ], anti-inflammatory [ 21 , 22 , 23 , 24 , 25 ], anti-microbial [ 26 , 27 , 28 ], anti-cancer [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], anti-convulsant [ 37 , 38 , 39 , 40 ], anti-analgesic [ 41 , 42 ], anti-tubercular [ 43 , 44 , 45 ], anti-hypertensive [ 3 , 46 ], anti-diabetic [ 47 ], anti-depressant [ 48 , 49 ], anti-Alzheimer’s [ 50 , 51 ], phosphodiesterase [ 52 , 53 ], platelet aggregation [ 54 , 55 , 56 , 57 ], and cholesterol acyl transferase inhibitor properties [ 58 ]. Peptide nucleic acids (PNAs) with new pyridazine-type nucleobases were reported as replacements for the DNA duplex bases instead of thymine, adenine, guanine and cytosine to form novel DNA or RNA duplexes [ 59 ].…”

Targeting Sterol O-Acyltransferase/Acyl-CoA:Cholesterol Acyltransferase (ACAT): A Perspective on Small-Molecule Inhibitors and Their Therapeutic Potential

“…A further indication that the alkyl chain and the phenyl group may only confer activity when they are orthogonally orientated on the central ring is the absence of inhibitory characteristics in the meta-and para-compounds. 107 The Pharmaceutical Division of Tokyo New Drug Research Laboratories concentrated on the development of a selective inhibitor of SOAT1 that could directly act on the arterial wall and suppress the development of atherosclerosis in an animal model without affecting plasma total cholesterol levels, considering the unsuccessful clinical trial of nonselective SOAT inhibitors. By using the double-induced fit mechanism for the viable development of an SOAT1-selective inhibitor, SAR development identified 9-(benzo[d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl) nonanamide (30, IC 50 = 0.004 μM toward aortic SOAT) as a potent SOAT inhibitor by conjugating two weak ligands, i.e., N-(2,6-diisopropylphenyl)acetamide (Figure 12) (IC 50 = 8.6 μM) and 2-(methylthio)benzo[d]oxazole (IC 50 = 31 μM), with a six-carbon methylene linker.…”

“…It is crucial that the carbonyl groups in molecules 27 and 28 have a specific function in the interaction at the enzyme’s active site that is not permitted for the corresponding amines (Figure ). A further indication that the alkyl chain and the phenyl group may only confer activity when they are orthogonally orientated on the central ring is the absence of inhibitory characteristics in the meta - and para -compounds …”