Inhibitors of acyl-CoA:cholesterol acyltransferase. 5. Identification and structure-activity relationships of novel .beta.-keto amides as hypocholesterolemic agents

Abstract

A study of structure-activity relationships of substituted beta-ketoamide ACAT inhibitors I and II was performed. The results of this study suggest that whereas the beta-keto group was tolerated with no loss in activity, beta-hydroxy and oxime moieties led to significantly reduced activity in vitro and in vivo. The most potent inhibitor from the acyclic series (I) (11, IC50 = 0.006 microM) contained a C-13 alkyl chain. This compound reduced plasma total cholesterol by 38% and 66% at 3 and 30 mg/kg, respectively, in cholesterol-fed rats. Dimethylation alpha to the anilide core (5) and subsequent N-methylation of the amide NH (6) decreased in vitro potency significantly. It was also found that high potency was retained with inhibitors which incorporated the carbonyl into a lactam ring (II).

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

“…Therefore, the urea moiety was an acceptable bioisosteric replacement for the amide . Later the same group extended this original fatty acid amide series to encompass β-ketoamides . A simple series of N , N ′-diphenylurea derivatives were also found to be potent ACAT inhibitors .…”

Synthesis of 4-Alkyl- and 4-(ω-Chloroalkyl)-3-hydroxy-5-alkylidenebuten­olides Based On Cyclizations of 4-Alkyl- and 4-(ω-Chloroalkyl)-1,3-bis(tri­methylsilyloxy)buta-1,3-dienes with Oxalyl Chloride

“…The syntheses of compounds 2b-h, [9][10][11][12][13][14] 3a and 4a, 2c and (2Z)-ethyl 2-[3-ethyl-4-hydroxy-5-oxofuran-2(5H)-ylidene]acetate (5a) 3b have been reported previously. 3b…”

“…Ethyl 3-Oxotetradecanoate (2h) 14 Ethyl acetoacetate ( 6,23.5,29.25,29.31,29.40,29.48,29.56,30.5,31.9,43.0,49.3 (CH 2 (9).…”

Application of the N-Dibenzyl Protective Group in the Preparation of β-Lactam Pseudopeptides

“…The β-lactam heterocycle is the main building block of the most broadly used antibacterial agents such as the penams (penicillin), penems, carbapenems, cephems and monobactams. Moreover, monocyclic β-lactams are potent cholesterol absorption inhibitors, which act through the inhibition of the enzyme cholesterol acyl transferase [1]. They are also dopamine receptor antagonists [2] and vasopressin V1a antagonists [3].…”