Inhibitors of Acyl-CoA:Cholesterol O-Acyl Transferase (ACAT) as Hypocholesterolemic Agents. 8. Incorporation of Amide or Amine Functionalities into a Series of Disubstituted Ureas and Carbamates. Effects on ACAT Inhibition in vitro and Efficacy in vivo

Abstract

A series of disubstituted ureas containing amide or amine groups was prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyl transferase in vitro and to lower plasma total cholesterol in a variety of cholesterol-fed rat models in vivo. The presence of polar or ionizable functionalities within this class of compounds may impart greater aqueous solubility to those compounds and thus allow improved transport to the enzyme location within the intestinal enterocyte. Compounds from this class exhibit good cholesterol lowering in a chronic cholesterol-fed rat model of hypercholesterolemia even when dosed in an aqueous vehicle. In general, the amine-containing compounds were more potent and efficacious than the amides in the acute rat model of hypercholesterolemia. Further structure-activity relationship studies showed that the preferred position of the amide/amine group was beta to the urea moiety and not alpha, and that in this series, the presence of a secondary amine (or amide) proton is required for good in vitro potency. One of these compounds, 9n(-), lowered plasma total cholesterol (-47%) and elevated high-density lipoprotein cholesterol (+256%) when dosed in an aqueous vehicle to rats with preestablished hypercholesterolemia.

Design, Synthesis and Biological Activity of New Polyenolic Inhibitors of Matrix Metalloproteinases: A Focus on Chemically-Modified Curcumins

“…The crude material was crystallized from a hexane:ethyl acetate (3:1) to afford 5p as a paleyellow crystalline solid, yield 46.0 %, mp 56-57 o C.(lit. [33]) 1 (7): 6d (0.426g, 1mmol) was added to 10mL ethyl acetate, followed by catalytic amount of 10% Pd/C. The reaction mixture was stirred under the atmosphere of H 2 for 2 hours, and then filtered through Celite.…”

Increased lanosterol turnover: a metabolic burden for daunorubicin-resistant leukemia cells

“…This did not turn out to be the case. However, terbinafine, an antifungal compound inhibiting SQLE, triparanol, an inhibitor of 24-dehydrocholesterol reductase (DHCR24), both shown to suppress tumor growth [ 20 – 23 ], as well as CI976, a potent and selective Acyl-CoA/cholesterol acyltransferase (SOAT1) inhibitor [ 24 , 25 ] did affect CEM/R2 more than the sensitive CEM cells (Fig. 2 a).…”

Enantioselective Aza‐Henry Reactions Assisted by ZnII and N‐Methylephedrine

“…The addition reaction of nitro compounds to azomethine functions, known as the aza‐Henry (or nitro‐Mannich) reaction,1 is a highly valuable CC bond‐forming process. The resulting 1,2‐nitroamine adducts can be transformed into 1,2‐diamines2 by reduction3 as well as α‐amino acids by a Nef oxidation 4. Whereas the production of both families of target molecules in nonracemic form bears considerable interest, the use of the aza‐Henry approach in that endeavor remains largely unexplored because of the long‐standing lack of (catalytic) asymmetric versions 1.…”

“…The elaboration of thus‐obtained aza‐Henry products into 1,2‐diamines and amino acids, respectively, could be performed using known procedures. For example, reduction of the nitro group in 8 a led to the known monoprotected diamine 9 ,15 while Nef oxidation under the conditions described by Mioskowski and co‐workers16 followed by methylation afforded the N ‐Boc‐protected ( R )‐phenylglycine methyl ester 12 without apparent loss of optical integrity (Scheme ) 17. Further acetylation of 9 to the known compound 10 allowed the absolute configuration of the adducts to be confirmed.…”