ABSTRACT
The synthesis, SAR, and in vivo activity of inhibitors of delta-5 desaturase are described. Ring-constraint of the initial series provided access to a variety of in vitro active chemotypes, from which the indazole was selected. Examples from the indazole series displayed in vivo activity in reducing the enzymatic activity of liver delta-5 desaturase.
Subject(s)
Amides/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Fatty Acid Desaturases/antagonists & inhibitors , Metabolic Syndrome/drug therapy , Amides/chemical synthesis , Amides/chemistry , Animals , Delta-5 Fatty Acid Desaturase , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Fatty Acid Desaturases/metabolism , Humans , Liver/enzymology , Metabolic Syndrome/enzymology , Metabolic Syndrome/metabolism , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.
Subject(s)
Aminopyridines/chemistry , Analgesics/chemistry , Pain/drug therapy , TRPV Cation Channels/antagonists & inhibitors , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Body Temperature/drug effects , CHO Cells , Calcium/metabolism , Capsaicin/pharmacology , Cricetulus , Freund's Adjuvant , Ganglia, Spinal/cytology , Humans , Hydrogen-Ion Concentration , Male , Pain/etiology , Rats, Sprague-Dawley , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/physiology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydrothiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC50 for GCPII following oral administration of 5 in rats. Consistent with the oral plasma pharmacokinetics, thiolactone 5 exhibited efficacy in a rat model of neuropathic pain following oral administration.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Glutamate Carboxypeptidase II/antagonists & inhibitors , Lactones/chemical synthesis , Prodrugs/chemical synthesis , Animals , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Lactones/pharmacology , Lactones/therapeutic use , Microsomes, Liver/metabolism , Neuralgia/drug therapy , RatsABSTRACT
A series of N-substituted 3-(2-mercaptoethyl)-1H-indole-2-carboxylic acids were synthesized as inhibitors of glutamate carboxypeptidase II (GCPII). Those containing carboxybenzyl or carboxyphenyl groups at the N-position exhibited potent inhibitory activity against GCPII. These indole-based compounds represent the first example of achiral GCPII inhibitors and demonstrate greater tolerance of the GCPII active site for ligands with significant structural difference from the endogenous substrate, N-acetyl-aspartylglutamate.
Subject(s)
Glutamate Carboxypeptidase II/antagonists & inhibitors , Indoles/chemistry , Protease Inhibitors/chemistry , Carboxylic Acids , Drug Evaluation, Preclinical , Glutamate Carboxypeptidase II/metabolism , Indoles/chemical synthesis , Indoles/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Two representative glutamate carboxypeptidase II (GCP II) inhibitors, 2-(hydroxypentafluorophenylmethyl-phosphinoylmethyl)pentanedioic acid 2 and 2-(3-mercaptopropyl)pentanedioic acid 3, were synthesized in high optical purities (>97%ee). The two enantiomers of 2 were prepared from previously reported chiral intermediates, (R)- and (S)-2-(hydroxyphosphinoylmethyl)pentanedioic acid benzyl esters 8. The synthesis of (R)- and (S)-3 involves the hydrolysis of (R)- and (S)-3-(2-oxo-tetrahydro-thiopyran-3-yl)propionic acids, (R)- and (S)-11, the corresponding optically pure thiolactones delivered by chiral chromatographic separation of the racemic 11. GCP II inhibitory assay revealed that (S)-2 is 40-fold more potent than (R)-2. In contrast, both enantiomers of 3 inhibited GCP II with nearly equal potency. The efficacy observed in subsequent animal studies with these enantiomers correlated well with the inhibitory potency in a GCP II assay.
