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1.
Bioorg Med Chem ; 18(5): 1822-33, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20172734

ABSTRACT

Finding small non-peptide molecules for G protein-coupled receptors (GPCR) whose endogenous ligands are peptides, is a very important task for medicinal chemists. Over the years, compounds mimicking peptide structures have been discovered, and scaffolds emulating peptide backbones have been designed. In our work on GPCR ligands, including cholecystokinin receptor-1 (CCKR-1) agonists, we have employed benzodiazepines as a core structure. Looking for ways to reduce molecular weight and possibly improve physical properties of GPCR ligands, we embarked on the search for molecules providing similar scaffolds to the benzodiazepine with lower molecular weight. One of our target core structures was 1,4-dihydro-[1,4]diazepine-5,7-dione. There was not, however, a known synthetic route to such molecules. Here we report the discovery of a simple and concise method for synthesis of 2-[6-(1H-indazol-3-ylmethyl)-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-[1,4]diazepin-1-yl]-N-isopropyl-N-phenyl-acetamide as an example of a compound containing the tetrahydrodiazepine-5,7-dione core. Compounds from this series were tested in numerous GPCR assays and demonstrated activity at melanocortin 1 and 4 receptors (MC1R and MC4R). Selected compounds from this series were tested in vivo in Peptide YY (PYY)-induced food intake. Compounds dosed by intracerebroventricular and oral routes reduced PYY-induced food intake and this effect was reversed by the cyclic peptide MC4R antagonist SHU9119.


Subject(s)
Azepines/chemical synthesis , Ligands , Melanocyte-Stimulating Hormones/chemical synthesis , Receptor, Melanocortin, Type 1/agonists , Receptor, Melanocortin, Type 4/agonists , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Azepines/chemistry , Azepines/pharmacokinetics , Benzodiazepines/chemistry , Circular Dichroism , Eating/drug effects , Melanocyte-Stimulating Hormones/chemistry , Melanocyte-Stimulating Hormones/pharmacokinetics , Peptides/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 1/metabolism , Receptor, Melanocortin, Type 4/metabolism , Receptors, G-Protein-Coupled/metabolism , Stereoisomerism , Structure-Activity Relationship
3.
J Med Chem ; 51(15): 4632-40, 2008 Aug 14.
Article in English | MEDLINE | ID: mdl-18620382

ABSTRACT

Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.


Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Cells, Cultured , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Humans , Indazoles , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Mice , Models, Molecular , Molecular Structure , Neoplasms/blood supply , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Receptors, Vascular Endothelial Growth Factor/chemistry , Receptors, Vascular Endothelial Growth Factor/metabolism , Sulfonamides/therapeutic use , Xenograft Model Antitumor Assays
4.
Chirality ; 19(9): 731-40, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17575572

ABSTRACT

GT-2331 [(+)-1] is one of the most potent members of a class of chiral drug substances used to regulate the synthesis and release of histamine by the histamine H3 receptor, and as such, is an important biomarker for pharmaceutical companies conducting research in this field. In addition to overall structural features, the bioactivity of this molecule has also been found to be highly dependent on absolute stereochemistry, making the reliable assignment of this property a necessity. X-ray diffraction studies have provided conflicting data, leaving its three-dimensional structure uncertain. In view of this, its absolute configuration was investigated by vibrational circular dichroism. Results from this study provided independent assignment of this important molecule as the (1S,2S)-enantiomer.


Subject(s)
Chemistry, Pharmaceutical/methods , Circular Dichroism/methods , Histamine Antagonists/chemistry , Imidazoles/pharmacology , Receptors, Histamine H3/chemistry , Dimerization , Drug Design , Humans , Hydrogen Bonding , Models, Chemical , Molecular Conformation , Spectrophotometry, Infrared/methods , Stereoisomerism , Thermodynamics , X-Ray Diffraction
5.
Peptides ; 24(5): 709-16, 2003 May.
Article in English | MEDLINE | ID: mdl-12895657

ABSTRACT

The lack of specific pharmacological tools has impeded the evaluation of the role of each melanocortin receptor (MCR) subtype in the myriad physiological effects of melanocortins. 154N-5 is an octapeptide (MFRdWFKPV-NH(2)) that was first identified as an MC1R antagonist in Xenopus melanophores [J. Biol. Chem. 269 (1994) 29846]. In this manuscript, we show that 154N-5 is a specific agonist for human and murine MC1R. The peptide has negligible activity at MC3R and MC4R and is 25-fold less potent and a weak agonist at MC5R. 154N-5 was tested in both a cellular and an animal model of tumor necrosis factor-alpha (TNF-alpha) secretion. The inhibitory efficacy of 154N-5 on TNF-alpha secretion in both models was similar to the nonselective agonist NDP-alpha-melanocyte stimulating hormone (NDP-alphaMSH), thus, we conclude that inhibition of TNF-alpha secretion by melanocortin peptides is mediated by MC1R. 154N-5 is a valuable new tool for the evaluation of specific contribution of MC1R agonism to physiological and pathological processes.


Subject(s)
Peptide Fragments/pharmacology , Receptor, Melanocortin, Type 1/agonists , Tumor Necrosis Factor-alpha/biosynthesis , Animals , Cell Line , Dose-Response Relationship, Drug , Female , Humans , Ligands , Lipopolysaccharides/pharmacology , Mice , Peptide Fragments/agonists , Peptide Fragments/chemistry , RNA, Messenger/metabolism , Receptor, Melanocortin, Type 1/analysis , Receptors, Melanocortin/agonists
6.
J Med Chem ; 46(16): 3476-82, 2003 Jul 31.
Article in English | MEDLINE | ID: mdl-12877585

ABSTRACT

Intermolecular interactions were determined between a synthetic peptide corresponding to the third extracellular loop and several residues from the adjoining sixth and seventh transmembrane domains of the human cholecystokinin-1 receptor, CCK(1)-R(329-357), and the synthetic agonists Ace-Trp-Lys[NH(epsilon)CONH-o-(MePh)]-Asp-MePhe-NH(2) (GI5269) and the C1 N-isopropyl-N-(4-methoxyphenyl)acetamide derivative of 3-(1H-Indazol-3ylmethyl)-3-methyl-5-pyridin-3-yl-1,5-benzodiazepine (GI0122), using high-resolution nuclear magnetic resonance spectroscopy and computer simulations. Addition of the ligands to CCK(1)-R(329-357) in an aqueous solution of DPC micelles produced a number of intermolecular nuclear Overhauser enhancements (NOEs) to residues in TMs 6 and 7 of the receptor fragment. NOE-restrained molecular models of the GI5269 and GI0122/CCK(1)-R complexes provide evidence for overlapping ligand-binding sites for peptidic and nonpeptidic agonists. The proposed binding modes of GI5269 and GI0122 are supported by the structure-activity relationship of analogues and mutagenesis data for the CCK(1)-R selective antagonist L-364,718.


Subject(s)
Benzodiazepinones/chemistry , Oligopeptides/chemistry , Receptors, Cholecystokinin/agonists , Receptors, Cholecystokinin/chemistry , Binding Sites , Computer Simulation , Devazepide/chemistry , Humans , Isomerism , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Mutation , Peptide Fragments/chemistry , Receptor, Cholecystokinin A , Receptors, Cholecystokinin/antagonists & inhibitors , Structure-Activity Relationship
7.
Curr Top Med Chem ; 3(8): 837-54, 2003.
Article in English | MEDLINE | ID: mdl-12678836

ABSTRACT

Almost 30 years have passed since Gibbs, Young, and Smith demonstrated the ability of exogenously administered cholecystokinin (CCK) to inhibit food intake in rats. This observation was the beginning of very extensive studies into the role CCK plays in the regulation of food intake in mammals. CCK is a brain-gut peptide, which exists in multiple forms. CCK peptides exert their action on two distinct receptor subtypes: CCK-A (Alimentary) now called the CCK1R, mostly expressed peripherally; and CCK-B (Brain), renamed the CCK2R, which is primarily present in the brain. Through the use of subtype-selective agonists and antagonists for the CCK receptor, it was determined that the effect of CCK on feeding was dependent on agonist induced activation of peripheral CCK1 receptors. This discovery was followed by intense research with the goal of identifying small molecule agonists on the CCK1 receptor as potentially useful agents for the treatment of obesity. This review will attempt to summarize the results of this research.


Subject(s)
Chemokines/agonists , Obesity/drug therapy , Chemokines, CC , Humans
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