Novel trifluoroacetophenone derivatives as malonyl-CoA decarboxylase inhibitors.

A series of trifluoroacetophenone derivatives were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Some of the 'reverse amide' analogs were found to be potent inhibitors of MCD enzyme activity. The trifluoroacetyl group may interact with the MCD active site as the hydrate in a similar fashion to the hexafluoroisopropanol analogs reported previously.

Discovery of potent and orally available malonyl-CoA decarboxylase inhibitors as cardioprotective agents.

Discovery of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamides as a new class of malonyl-coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamido)butanoate (5, CBM-301940) exhibited excellent potency and in vivo PK/ADME properties. It is the most powerful stimulant of glucose oxidation reported to date in isolated working rat hearts.

Heteroaryl substituted bis-trifluoromethyl carbinols as malonyl-CoA decarboxylase inhibitors.

A series of heteroaryl-substituted bis-trifluoromethyl carbinols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Some thiazole-based derivatives showed potent in vitro MCD inhibitory activities and significantly increased glucose oxidation rates in isolated working rat hearts.

Synthesis and structure-activity relationship of small-molecule malonyl coenzyme A decarboxylase inhibitors.

The discovery and structure-activity relationship of first-generation small-molecule malonyl-CoA decarboxylase (MCD; CoA = coenzyme A) inhibitors are reported. We demonstrated that MCD inhibitors increased malonyl-CoA concentration in the isolated working rat hearts. Malonyl-CoA is a potent, endogenous, and allosteric inhibitor of carnitine palmitoyltransferase-I (CPT-I), a key enzyme for mitochondrial fatty acid oxidation.

Aza-retinoids as novel retinoid X receptor-specific agonists.

A new structurally simple series of potent lipophilic aza-retinoids RXR agonists has been developed. SAR studies for the N-alkyl-azadienoic acids described here demonstrate that the RXR activity profile is sensitive to the N-alkyl chain length. Further, we have expanded the work to include azadienoic acids, which exhibited many accessible conformations leading to a better understanding of the SAR around the series.

Design and synthesis of heterocyclic malonyl-CoA decarboxylase inhibitors.

We have previously reported the discovery of small molecule inhibitors of malonyl-CoA decarboxylase (MCD) as novel metabolic modulators, which inhibited fatty acid oxidation and consequently increased the glucose oxidation rates in the isolated working rat hearts. MCD inhibitors were also shown to improve cardiac efficiency in rat and pig demand-induced ischemic models through the mechanism-based modulation of energy metabolism. Herein, we describe the design and synthesis of a series of novel heterocyclic MCD inhibitors with a preference for substituted imidazole and isoxazole.

Discovery and structure-activity relationship of coumarin derivatives as TNF-alpha inhibitors.

The discovery and structure-activity relationship of a novel series of coumarin-based TNF-alpha inhibitors is described. Starting from the initial lead 1a, various derivatives were prepared surrounding the coumarin core structure to optimize the in vitro inhibitory activity of TNF-alpha production by human peripheral blood mononuclear cells (hPBMC), stimulated by bacterial lipopolysaccharide (LPS). Selected compounds also demonstrated in vivo inhibition of TNF-alpha production in rats.

Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation.

Abnormally high rates of fatty acid oxidation and low rates of glucose oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA.

Expression, purification, and characterization of human malonyl-CoA decarboxylase.

The recombinant human malonyl-CoA decarboxylase (hMCD) was overexpressed in Escherichia coli with and without the first 39 N-terminal amino acids via a cleavable MBP-fusion construct. Proteolytic digestion using genenase I to remove the MBP-fusion tag was optimized for both the full length and truncated hMCD. The apo-hMCD enzymes were solubilized and purified to homogeneity.

Novel chromene derivatives as TNF-alpha inhibitors.

A novel series of chromene-based TNF-alpha inhibitors is described. These chromene derivatives inhibit bacterial lipopolysaccharide (LPS) stimulated production of TNF-alpha from human peripheral blood mononuclear cells (PBMC). Additionally, these compounds inhibit NF-kB mediated transcription activation.

Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.

A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.

Synthesis and Characterization of a Highly Potent and Selective Isotopically Labeled Retinoic Acid Receptor Ligand, ALRT1550.

The syntheses of two labeled homologues of (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2,4,6-trienoic acid (ALRT1550, 2), [(13)CD(3)]ALRT1550 (3) and [(3)H]ALRT1550 (4), are described in this report. ALRT1550 is an exceptionally potent antiproliferative agent which is currently in phase I/II clinical trials for acute chemotherapy. Both homologues were prepared from commercially available 3,5-di-tert-butylbenzoic acid.