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1.
J Med Chem ; 61(22): 9889-9907, 2018 11 21.
Article in English | MEDLINE | ID: mdl-30346772

ABSTRACT

The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.


Subject(s)
Antineoplastic Agents/pharmacology , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Sulfoxides/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Chemical Phenomena , Clinical Trials as Topic , Female , Humans , Indoles , Mice , Models, Molecular , Molecular Conformation , Morpholines , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Sulfonamides , Sulfoxides/chemistry , Sulfoxides/pharmacokinetics , Tissue Distribution
2.
Medchemcomm ; 7(8): 1580-1586, 2016 Aug 01.
Article in English | MEDLINE | ID: mdl-27746890

ABSTRACT

Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 µM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine 25 was also shown to have high potency against the CDK9 enzyme (3 nM).

3.
J Med Chem ; 59(6): 2346-61, 2016 Mar 24.
Article in English | MEDLINE | ID: mdl-26878898

ABSTRACT

Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the "housekeeping" enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , DNA Repair Enzymes/antagonists & inhibitors , Phosphoric Monoester Hydrolases/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Discovery , Humans , Models, Molecular , RNA, Small Interfering/pharmacology , Rats , Structure-Activity Relationship
4.
Future Med Chem ; 7(7): 873-91, 2015.
Article in English | MEDLINE | ID: mdl-26061106

ABSTRACT

In this article, we review the ATR inhibitor field from initial pharmacological tools to first-generation clinical candidates with the potential to bring benefit to cancer patients. ATR is a critical part of the cell DNA-damage response. Over the past decade or more, compounds with weak ATR potency and low specificity have been used as tools in early studies to elucidate ATR pharmacology. More recently highly potent, selective and in vivo active ATR inhibitors have been developed enabling detailed preclinical in vitro and in vivo target assessment to be made. The published studies reveal the potential of ATR inhibitors for use as monotherapy or in combination with DNA-damaging agents. To date, VX-970 and AZD6738, have entered clinical assessment.


Subject(s)
Antineoplastic Agents/pharmacology , Isoxazoles/pharmacology , Neoplasms/drug therapy , Pyrazines/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Ataxia Telangiectasia Mutated Proteins/metabolism , DNA Damage , Humans , Isoxazoles/chemistry , Isoxazoles/therapeutic use , Molecular Conformation , Pyrazines/chemistry , Pyrazines/therapeutic use
5.
Chirality ; 25(11): 692-700, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23893707

ABSTRACT

Dimethylaluminum triflate-mediated activation of tetrafluorobenzoates of enantiomerically pure bromohydrins results in enantiospecific polyene cyclizations. The initiation of cyclization by enantiomerically pure bromonium ions and subsequent propagation is not subject to catastrophic erosion of enantiomeric purity by any intramolecular or intermolecular bromonium ion-to-alkene transfer.


Subject(s)
Alcohols/chemistry , Polyenes/chemistry , Cyclization , Stereoisomerism , Substrate Specificity
6.
J Med Chem ; 56(5): 2125-38, 2013 Mar 14.
Article in English | MEDLINE | ID: mdl-23394205

ABSTRACT

ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.


Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Morpholines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Animals , Antineoplastic Agents/therapeutic use , Ataxia Telangiectasia Mutated Proteins , Crystallography, X-Ray , Drug Discovery , Female , HeLa Cells , Humans , Mice , Models, Molecular , Morpholines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Structure-Activity Relationship , Xenograft Model Antitumor Assays
7.
J Med Chem ; 55(11): 5003-12, 2012 Jun 14.
Article in English | MEDLINE | ID: mdl-22612866

ABSTRACT

The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.


Subject(s)
Pyrazoles/chemistry , Pyrimidines/chemistry , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Animals , Binding Sites , Crystallography, X-Ray , Dimerization , Drug Design , Humans , Ligands , Mice , Mice, Knockout , Models, Molecular , Molecular Structure , Phosphorylation , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/chemistry , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 18(6): 1904-9, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-18294849

ABSTRACT

A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume.


Subject(s)
Colonic Neoplasms/drug therapy , Protein Kinase Inhibitors/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemistry , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Aurora Kinase B , Aurora Kinases , Cell Cycle/drug effects , Colonic Neoplasms/enzymology , Colonic Neoplasms/pathology , Cytochrome P-450 CYP3A/metabolism , Electrophysiology , Ether-A-Go-Go Potassium Channels/metabolism , Histones/metabolism , Humans , Male , Mice , Mice, Nude , Molecular Structure , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/metabolism , Quinazolines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
9.
Bioorg Med Chem Lett ; 17(23): 6448-54, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17937987

ABSTRACT

A new class of small-molecule GnRH antagonists, the thieno[2,3-b]pyrroles, was designed. Herein, the synthesis and structure-activity relationships are described. Substitution at the C4 position was investigated; during this study, it was observed that introducing piperazines and piperidines improved the physical properties of the compounds while retaining good in vitro potency. This exploration led to the discovery of amidopiperidines with improved pharmacokinetic properties.


Subject(s)
Pyrroles/chemical synthesis , Receptors, LHRH/antagonists & inhibitors , Thiophenes/chemical synthesis , Animals , Humans , Pyrroles/pharmacology , Rats , Receptors, LHRH/metabolism , Receptors, LHRH/physiology , Structure-Activity Relationship , Thiophenes/pharmacology
10.
Clin Cancer Res ; 13(12): 3682-8, 2007 Jun 15.
Article in English | MEDLINE | ID: mdl-17575233

ABSTRACT

PURPOSE: In the current study, we examined the in vivo effects of AZD1152, a novel and specific inhibitor of Aurora kinase activity (with selectivity for Aurora B). EXPERIMENTAL DESIGN: The pharmacodynamic effects and efficacy of AZD1152 were determined in a panel of human tumor xenograft models. AZD1152 was dosed via several parenteral (s.c. osmotic mini-pump, i.p., and i.v.) routes. RESULTS: AZD1152 potently inhibited the growth of human colon, lung, and hematologic tumor xenografts (mean tumor growth inhibition range, 55% to > or =100%; P < 0.05) in immunodeficient mice. Detailed pharmacodynamic analysis in colorectal SW620 tumor-bearing athymic rats treated i.v. with AZD1152 revealed a temporal sequence of phenotypic events in tumors: transient suppression of histone H3 phosphorylation followed by accumulation of 4N DNA in cells (2.4-fold higher compared with controls) and then an increased proportion of polyploid cells (>4N DNA, 2.3-fold higher compared with controls). Histologic analysis showed aberrant cell division that was concurrent with an increase in apoptosis in AZD1152-treated tumors. Bone marrow analyses revealed transient myelosuppression with the drug that was fully reversible following cessation of AZD1152 treatment. CONCLUSIONS: These data suggest that selective targeting of Aurora B kinase may be a promising therapeutic approach for the treatment of a range of malignancies. In addition to the suppression of histone H3 phosphorylation, determination of tumor cell polyploidy and apoptosis may be useful biomarkers for this class of therapeutic agent. AZD1152 is currently in phase I trials.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Neoplasms, Experimental/drug therapy , Organophosphates/pharmacology , Quinazolines/pharmacology , Animals , Aurora Kinase B , Aurora Kinases , Cell Line, Tumor , Cell Proliferation/drug effects , Flow Cytometry , Humans , Mice , Mice, Nude , Protein Serine-Threonine Kinases/drug effects , Rats , Transplantation, Heterologous
11.
J Med Chem ; 50(9): 2213-24, 2007 May 03.
Article in English | MEDLINE | ID: mdl-17373783

ABSTRACT

The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.


Subject(s)
Antineoplastic Agents/chemical synthesis , Organophosphates/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Quinazolines/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Aurora Kinase A , Aurora Kinase B , Aurora Kinases , Cell Division/drug effects , Cell Line, Tumor , Cytochrome P-450 Enzyme Inhibitors , Drug Screening Assays, Antitumor , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/drug effects , Female , Histones/metabolism , Humans , Male , Mice , Mice, Nude , Organophosphates/pharmacokinetics , Organophosphates/pharmacology , Phosphorylation , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Protein Binding , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Rats , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship , Transplantation, Heterologous
12.
J Cell Sci ; 119(Pt 17): 3664-75, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16912073

ABSTRACT

The Aurora kinases, a family of mitotic regulators, have received much attention as potential targets for novel anti-cancer therapeutics. Several Aurora kinase inhibitors have been described including ZM447439, which prevents chromosome alignment, spindle checkpoint function and cytokinesis. Subsequently, ZM447439-treated cells exit mitosis without dividing and lose viability. Because ZM447439 inhibits both Aurora A and B, we set out to determine which phenotypes are due to inhibition of which kinase. Using molecular genetic approaches, we show that inhibition of Aurora B kinase activity phenocopies ZM447439. Furthermore, a novel ZM compound, which is 100 times more selective for Aurora B over Aurora A in vitro, induces identical phenotypes. Importantly, inhibition of Aurora B kinase activity induces a penetrant anti-proliferative phenotype, indicating that Aurora B is an attractive anti-cancer drug target. Using molecular genetic and chemical-genetic approaches, we also probe the role of Aurora A kinase activity. We show that simultaneous repression of Aurora A plus induction of a catalytic mutant induces a monopolar phenotype. Consistently, another novel ZM-related inhibitor, which is 20 times as potent against Aurora A compared with ZM447439, induces a monopolar phenotype. Expression of a drug-resistant Aurora A mutant reverts this phenotype, demonstrating that Aurora A kinase activity is required for spindle bipolarity in human cells. Because small molecule-mediated inhibition of Aurora A and Aurora B yields distinct phenotypes, our observations indicate that the Auroras may present two avenues for anti-cancer drug discovery.


Subject(s)
Antineoplastic Agents/metabolism , Benzamides/metabolism , Neoplasms/therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Quinazolines/metabolism , Animals , Antineoplastic Agents/chemistry , Aurora Kinase B , Aurora Kinases , Benzamides/chemistry , Cell Division/physiology , Cell Polarity , Cell Proliferation , Cell Survival , Drug Design , Humans , Molecular Sequence Data , Molecular Structure , Phenotype , Protein Serine-Threonine Kinases/genetics , Quinazolines/chemistry , Spindle Apparatus/metabolism
13.
Curr Top Med Chem ; 5(8): 807-21, 2005.
Article in English | MEDLINE | ID: mdl-16101420

ABSTRACT

Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anti-cancer agents. The Aurora kinases represent one such family of mitotic regulators. In recent years there has been intense interest in both understanding the role of the Aurora kinases in cell cycle regulation and also in developing small molecule inhibitors as potential novel anti-cancer drugs. With several companies now starting to take Aurora kinase inhibitors into clinical development, the time is right to review the medicinal chemistry contribution to developing the field, in particular to review the increasingly broad range of small molecule inhibitors with activity against this kinase family.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Neoplasms/enzymology , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/physiology , Structure-Activity Relationship
14.
Curr Top Med Chem ; 5(2): 199-213, 2005.
Article in English | MEDLINE | ID: mdl-15853647

ABSTRACT

Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anti-cancer agents. The Aurora kinases represent one such family of mitotic regulators. In recent years there has been intense interest in both understanding the role of the Aurora kinases in cell cycle regulation and also in developing small molecule inhibitors as potential novel anti-cancer drugs. With several companies now starting to take Aurora kinase inhibitors into clinical development, the time is right to review the medicinal chemistry contribution to developing the field, in particular to review the increasingly broad range of small molecule inhibitors with activity against this kinase family.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Aurora Kinases , Humans , Models, Molecular , Neoplasms/enzymology , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/physiology , Structure-Activity Relationship
15.
Org Biomol Chem ; 1(22): 3917-48, 2003 Nov 21.
Article in English | MEDLINE | ID: mdl-14664383

ABSTRACT

A concise synthesis of the tricyclic furanochroman unit 3 found in the PAF antagonist phomactin A (1) isolated from the marine fungus Phoma sp., is described. In complementary studies, a variety of synthetic routes towards the bicyclo[9.3.1]pentadecane ring system 4 in phomactin A were explored. These studies culminated in a synthesis of the substituted ring system 79 containing all the carbon atoms and all the necessary oxygen centres for elaboration to phomactin A itself.


Subject(s)
Chromans/chemical synthesis , Furans/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxygen/chemistry , Alkanes/chemistry , Ascomycota/metabolism , Chemistry, Organic/methods , Furans/chemistry , Models, Chemical , Temperature
16.
J Med Chem ; 45(16): 3509-23, 2002 Aug 01.
Article in English | MEDLINE | ID: mdl-12139462

ABSTRACT

The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.


Subject(s)
Anti-Obesity Agents/chemical synthesis , Carbazoles/chemical synthesis , Morpholines/chemical synthesis , Receptors, Neuropeptide Y/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Aniline Compounds/toxicity , Animals , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/toxicity , Appetite Depressants/chemical synthesis , Appetite Depressants/pharmacology , Appetite Depressants/toxicity , Carbazoles/chemistry , Carbazoles/pharmacology , Carbazoles/toxicity , Dose-Response Relationship, Drug , Eating/drug effects , Fasting , Humans , Morpholines/chemistry , Morpholines/pharmacology , Mutagenicity Tests , Rats , Rats, Wistar , Structure-Activity Relationship , Urea/pharmacology , Urea/toxicity
17.
Diabetes ; 51(8): 2441-9, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12145156

ABSTRACT

Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of NPY have been ascribed to actions at the NPY Y5 receptor, we have determined the role of this receptor in feeding in rats, using a small molecule antagonist of this receptor. NPY5RA-972 is a selective and potent (<10 nmol/l) NPY Y5 receptor antagonist. This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC(50) (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats. Chronic administration of NPY5RA-972 (10 mg/kg twice daily) had no effect on food intake or body weight in either free-feeding Wistar rats or dietary obese rats. These data indicate that NPY5RA-972 is a potent, selective, orally active, and CNS-penetrant antagonist of the NPY Y5 receptor that prevents feeding driven by activation of this receptor. The data obtained with this antagonist indicate that the NPY Y5 receptor is not a major regulator of feeding in the rat.


Subject(s)
Appetite Depressants/pharmacology , Cyclobutanes/pharmacology , Feeding Behavior/physiology , Neuropeptide Y/pharmacology , Peptide Fragments/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Appetite Depressants/administration & dosage , Cerebral Ventricles/drug effects , Cerebral Ventricles/physiology , Cyclobutanes/administration & dosage , Energy Intake/drug effects , Feeding Behavior/drug effects , Injections, Intraventricular , Kinetics , Neuropeptide Y/administration & dosage , Peptide Fragments/administration & dosage , Rats , Rats, Wistar , Rats, Zucker
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