ABSTRACT
A series of Arg-Phe-NH2 peptidomimetics containing an Arg mimetic were synthesized and tested as agonists of human MrgX1, rat MrgC, and mouse MrgC11 receptors. As predicted from the previously established species specificity, these peptidomimetics were found to be devoid of MrgX1 agonist activity. In contrast, these compounds acted as agonists of MrgC and/or MrgC11 with varying degrees of potency. These new peptidomimetics should complement the existing small molecule human MrgX1 agonists and enhance our ability to assess the therapeutic utility of targeting Mrg receptors in rodent models.
Subject(s)
Neuropeptides/chemistry , Receptors, G-Protein-Coupled/agonists , Animals , HEK293 Cells , Humans , Mice , Neuropeptides/chemical synthesis , Neuropeptides/metabolism , Peptidomimetics/pharmacology , Protein Binding/drug effects , Rats , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , TransfectionABSTRACT
Several 2'-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2'-Deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism.
Subject(s)
Cytidine Deaminase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Tetrahydrouridine/analogs & derivatives , Tetrahydrouridine/chemical synthesis , Animals , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Biological Availability , Decitabine , Drug Design , Drug Stability , Enzyme Inhibitors/pharmacokinetics , Excitatory Postsynaptic Potentials , Fluorine , Gastric Juice/chemistry , Macaca mulatta , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Tetrahydrouridine/pharmacologyABSTRACT
Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure-activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenyl-acetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model.
Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glutaminase/antagonists & inhibitors , Sulfides/chemistry , Sulfides/pharmacology , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Magnetic Resonance Spectroscopy , Models, Molecular , Sulfides/chemical synthesis , Thiadiazoles/chemical synthesisABSTRACT
A series of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors have been synthesized with either a 3-(mercaptomethyl)benzoic acid or 2-(2-mercaptoethyl)benzoic acid scaffold. Potent inhibitors were identified from each of the two scaffolds with IC(50) values in the single-digit nanomolar range, including 2-(3-carboxybenzyloxy)-5-(mercaptomethyl)benzoic acid 27c and 3-(2-mercaptoethyl)biphenyl-2,3'-dicarboxylic acid 35c. Compound 35c was found to be metabolically stable and selective over a number of targets related to glutamate-mediated neurotransmission. Furthermore, compound 35c was found to be orally available in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.
Subject(s)
Benzoates/chemical synthesis , Benzoates/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glutamate Carboxypeptidase II/antagonists & inhibitors , Animals , Benzoates/pharmacokinetics , Benzoates/therapeutic use , Chemistry Techniques, Synthetic , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , 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
A series of thiol-based inhibitors containing a benzyl moiety at the P1' position have been synthesized and tested for their abilities to inhibit glutamate carboxypeptidase II (GCP II). 3-(2-Carboxy-5-mercaptopentyl)benzoic acid 6c was found to be the most potent inhibitor with an IC(50) value of 15 nM, 6-fold more potent than 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), a previously discovered, orally active GCP II inhibitor. Subsequent SAR studies have revealed that the phenoxy and phenylsulfanyl analogues of 6c, 3-(1-carboxy-4-mercaptobutoxy)benzoic acid 26a and 3-[(1-carboxy-4-mercaptobutyl)thio]benzoic acid 26b, also possess potent inhibitory activities toward GCP II. In the rat chronic constriction injury (CCI) model of neuropathic pain, compounds 6c and 26a significantly reduced hyperalgesia following oral administration (1.0 mg/kg/day).
Subject(s)
Analgesics/chemical synthesis , Benzoates/chemical synthesis , Glutamate Carboxypeptidase II/antagonists & inhibitors , Sulfhydryl Compounds/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Animals , Antigens, Surface , Benzoates/chemistry , Benzoates/pharmacology , Chronic Disease , Constriction, Pathologic , Glutarates/chemistry , Glutarates/pharmacology , Humans , Pain/drug therapy , Peripheral Nervous System Diseases/drug therapy , Rats , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacologyABSTRACT
A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC(50) = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.
