ABSTRACT
A series of novel spirocyclic DGAT1 inhibitors containing the oxadiazole motif were designed and synthesized for biological evaluation. Several compounds exhibited potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activity. Optimization of the series led to the identification of five lead compounds 8, 9, 10, 11 and 12 that showed excellent in-vitro activity with IC50 values ranging from 7 to 20 nM against human DGAT1. All compounds demonstrated good druggability as well as microsomal stability and safety profiles such as hERG and CYP. Compound 12 significantly reduced plasma triglyceride levels in-vivo in the mouse model of acute lipid challenge. Significant reduction in plasma TG excursion was observed, thus indicating DGAT1 inhibition in-vivo.
Subject(s)
Carboxylic Acids , Diacylglycerol O-Acyltransferase , Enzyme Inhibitors , Animals , Carboxylic Acids/pharmacology , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Disease Models, Animal , Drug Design , Enzyme Inhibitors/pharmacology , Mice , Oxadiazoles/pharmacology , TriglyceridesABSTRACT
Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.
Subject(s)
Adenosine A1 Receptor Antagonists/chemistry , Adenosine A1 Receptor Antagonists/pharmacology , Hypoxanthines/chemistry , Hypoxanthines/pharmacology , Adenosine A1 Receptor Antagonists/chemical synthesis , Adenosine A1 Receptor Antagonists/pharmacokinetics , Animals , Carbon-13 Magnetic Resonance Spectroscopy , Chromatography, Liquid , Drug Design , HEK293 Cells , Humans , Hypoxanthines/chemical synthesis , Hypoxanthines/pharmacokinetics , Male , Mass Spectrometry , Proton Magnetic Resonance Spectroscopy , Radioligand Assay , Rats , Rats, WistarABSTRACT
Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.
Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Carboxylic Acids/chemistry , Enzyme Inhibitors/chemistry , Pyrazoles/chemistry , Thiophenes/chemistry , Alcohol Oxidoreductases/metabolism , Animals , Binding Sites , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacokinetics , Computer Simulation , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Kidney/enzymology , Kidney/metabolism , Liver/enzymology , Liver/metabolism , Protein Structure, Tertiary , Pyrazoles/chemical synthesis , Pyrazoles/therapeutic use , Rats , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/therapeutic useABSTRACT
l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.
ABSTRACT
Three new triterpenoids, designated as acinospesigenin-A (1), -B (2), and -C (3), isolated from the berries of Phytolacca acinosa, have been characterized as 3 beta-acetoxy-11 alpha,23-dihydroxytaraxer-14-en-28-oic acid, olean-12-en-23-al-2 beta,3 beta-dihydroxy-30-methoxycarbonyl-28-oic acid and olean-12-en-23-al-2 beta,3 beta,11 alpha-trihydroxy-30-methoxycarbonyl-28-oic acid, respectively. The compounds have shown antiedemic activity (LD(50) 10-15 mg/kg mass) in albino rats.
Subject(s)
Phytolacca/chemistry , Plants, Medicinal/chemistry , Triterpenes/isolation & purification , Animals , Edema/drug therapy , Fruit/chemistry , Hindlimb/drug effects , India , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Plant Leaves/chemistry , Rats , Stereoisomerism , Triterpenes/chemistry , Triterpenes/pharmacologyABSTRACT
Four new alkaloids, characterized as 6-(2-hydroxyethyl)-5,6-dihydrosanguinarine (1), 6-acetonyl-5,6-dihydrosanguinarine (2), N-methyl-2,3,7,8-tetramethoxy-5,6-dihydrobenzophenanthridine-6-ethanoic acid (3), N-methyl-2,3,7,8-tetramethoxy-6-oxo-5,6-dihydrobenzophenanthridine (4), together with oxosanguinarine (5), spallidamine (6), 6-acetonyl-5,6-dihydrochelerythrine (7), 6-oxochelerythrine (8) and sanguidimerine (9) were isolated from the roots of Corydalis flabellata.
