Christian J. Mularski

Isozyme-nonselective N-Substituted Bipiperidylcarboxamide Acetyl-CoA Carboxylase Inhibitors Reduce Tissue Malonyl-CoA Concentrations, Inhibit Fatty Acid Synthesis, and Increase Fatty Acid Oxidation in Cultured Cells and in Experimental Animals

Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect the multitude of cardiovascular risk factors associated with the metabolic syndrome. To achieve maximal effectiveness, an ACC inhibitor should inhibit both the lipogenic tissue isozyme (ACC1) and the oxidative tissue isozyme (ACC2). Herein, we describe the biochemical and acute physiological properties of CP-610431, an isozyme-nonselective ACC inhibitor identified through high throughput inhibition screening, and CP-640186, an analog with improved metabolic stability. CP-610431 inhibited ACC1 and ACC2 with IC50s of ∼50 nm. Inhibition was reversible, uncompetitive with respect to ATP, and non-competitive with respect to bicarbonate, acetyl-CoA, and citrate, indicating interaction with the enzymatic carboxyl transfer reaction. CP-610431 also inhibited fatty acid synthesis, triglyceride (TG) synthesis, TG secretion, and apolipoprotein B secretion in HepG2 cells (ACC1) with EC50s of 1.6, 1.8, 3.0, and 5.7 μm, without affecting either cholesterol synthesis or apolipoprotein CIII secretion. CP-640186, also inhibited both isozymes with IC50sof ∼55 nm but was 2–3 times more potent than CP-610431 in inhibiting HepG2 cell fatty acid and TG synthesis. CP-640186 also stimulated fatty acid oxidation in C2C12 cells (ACC2) and in rat epitrochlearis muscle strips with EC50s of 57 nm and 1.3 μm. In rats, CP-640186 lowered hepatic, soleus muscle, quadriceps muscle, and cardiac muscle malonyl-CoA with ED50s of 55, 6, 15, and 8 mg/kg. Consequently, CP-640186 inhibited fatty acid synthesis in rats, CD1 mice, and ob/ob mice with ED50s of 13, 11, and 4 mg/kg, and stimulated rat whole body fatty acid oxidation with an ED50 of ∼30 mg/kg. Taken together, These observations indicate that isozyme-nonselective ACC inhibition has the potential to favorably affect risk factors associated with the metabolic syndrome.

Discovery of zoniporide: A potent and selective sodium–hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility

Zoniporide (CP-597,396) is a potent and selective inhibitor of NHE-1, which exhibits high aqueous solubility and acceptable pharmacokinetics for intravenous administration. The discovery, synthesis, activities, and rat and dog pharmacokinetics of this compound are presented. The potency and selectivity of zoniporide may be due to the conformation that the molecule adopts due to the presence of a cyclopropyl and a 5-quinolinyl substituent on the central pyrazole ring of the molecule.

The synthetic utility of p-nitrophenyl 3-bromo-2,2-diethoxypropionate

Abstract The synthesis of p -nitrophenyl 3-bromo-2,2-diethoxypropionate, and its chemoselective reactions for the preparation of highly functionalized small molecules and also novel heterocycles, are described.

The reaction of 5-acetyl-2-aminooxazole with amines: an approach to 1H-5-acetyl-2-aminoimidazoles

Abstract 5-Acetyl-2-aminooxazole, upon treatment with amines in the presence of water, affords good yields of 1H-5-acetyl-2-substituted amino-imidazoles, along witn varying amounts of the corresponding 5-hydroxy-4-methyl-2-substituted aminopyrimidines.

Synthesis and pharmacological profile of two novel heterocyclic chromanols, CP-80,798 and CP-85,958, as potent LTD4 receptor antagonists

Abstract The development of two novel LTD 4 receptor antagonists as clinical candidates for the treatment of asthma is described. The first generation compound, CP-80,798, was found to be a balanced 5-lipoxygenase inhibitor (5-LOI)/LTD 4 antagonist (LTD 4 -A), while the second generation compound, CP-85,958, is a selective LTD 4 antagonist.

Dihydropyridines: a new class of angiotensin II antagonists

Abstract The syntheses and biological activities of dihydropyridine angiotensin II (AII) antagonists are described. Compounds such as 12 are examples of a new, structurally distinct class of AT(in1-selective agents.

Synthesis of 2-amino-5-hydroxy-4-pyrimidones and 5,6-biheteroaryls using p-nitrophenyl 3-bromo-2,2-diethoxypropionate (NPBDP)

Abstract The reaction of NPBDP with various guanidines affords, after formic acid hydrolysis, 2-amino-5-hydroxy-4-pyrimidones. Reaction of NPBDP with o-aminoheterocycles gives similar results. NPBDP is readily converted to the 3-amino-2-alkenenitrile, 10, a key building block for the synthesis of 5,6-biheteroaryls.