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2.
Eur J Pharmacol ; 601(1-3): 1-7, 2008 Dec 28.
Article in English | MEDLINE | ID: mdl-18976648

ABSTRACT

The neuropeptide Y (NPY) Y(5) receptor is believed to be involved in the central regulation of appetite. Thus, antagonists of this receptor have been pursued as potential therapeutic agents for the treatment of obesity. A novel series of potent and selective phenylamide or biaryl urea NPY Y(5) receptor antagonists was identified. Four representative compounds from this series, SCH 208639 (N-[4-[(1,1-dimethylbutyl)thio]phenyl]-2,2-dimethylpropanamide), SCH 430765 (N-[[[3'-fluoro[1,1'-biphenyl]-4-yl]amino]carbonyl]-N-methyl-1-(methylsulfonyl)-4-piperidinamine), SCH 488106 (N-[[[3',5'-difluoro[1,1'-biphenyl]-4-yl]amino]carbonyl]-N-methyl-1-[(5-methyl-3-pyridinyl)carbonyl]-4-piperidinamine) and SCH 500946 (N-[[[5-(3,5-difluorophenyl)-2-pyrazinyl]amino]carbonyl]-N-methyl-1-(methylsulfonyl)-4-piperidinamine), behaved as competitive antagonists in radioligand binding assays, but displayed apparently insurmountable antagonism in a cell-based functional assay. The apparently insurmountable antagonism was due to slow receptor dissociation rates rather than covalent binding, because the antagonists' effects could be reduced by extensive washing of cells after antagonist exposure. A novel radioligand, [(35)S]SCH 500946, was also developed and used to characterize the interaction of these antagonists with the NPY Y(5) receptor. [(35)S]SCH 500946 had high affinity for the NPY Y(5) receptor (K(d)=0.29 nM), and the binding kinetics (k(on) 4.414 x 10(7) M(-)(1) min(-1); k(off) 0.009816 min(-1)) confirmed that the compound slowly dissociates from the receptor. In a competition binding assay, NPY failed to displace [(35)S]SCH 500946 completely, indicating that the binding sites for NPY and [(35)S]SCH 500946 are not identical. These data indicate that the apparent insurmountable antagonism of these NPY Y(5) receptor antagonists is attributable both to slow receptor dissociation rates and to binding at a site distinct from NPY.


Subject(s)
Piperidines/pharmacology , Radioligand Assay/methods , Radiopharmaceuticals/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Amides/pharmacology , Animals , Binding Sites , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Humans , Rats , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 17(13): 3760-4, 2007 Jul 01.
Article in English | MEDLINE | ID: mdl-17466519

ABSTRACT

Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.


Subject(s)
Chemistry, Pharmaceutical/methods , Receptor, Cannabinoid, CB2/chemistry , Sulfones/chemistry , Animals , Drug Design , Drug Evaluation, Preclinical , Kinetics , Ligands , Models, Chemical , Protein Binding , Rats , Receptors, Drug , Sodium/chemistry , Structure-Activity Relationship
4.
Virology ; 349(1): 41-54, 2006 May 25.
Article in English | MEDLINE | ID: mdl-16494916

ABSTRACT

The CC-chemokine receptor 5 (CCR5) is the major coreceptor for macrophage-tropic (R5) HIV-1 strains. Several small molecule inhibitors of CCR5 that block chemokine binding and HIV-1 entry are being evaluated as drug candidates. Here we define how CCR5 antagonists TAK-779, AD101 (SCH-350581) and SCH-C (SCH-351125), which inhibit HIV-1 entry, interact with CCR5. Using a mutagenesis approach in combination with a viral entry assay to provide a direct functional read out, we tested predictions based on a homology model of CCR5 and analyzed the functions of more than 30 amino acid residues. We find that a key set of aromatic and aliphatic residues serves as a hydrophobic core for the ligand binding pocket, while E283 is critical for high affinity interaction, most likely by acting as the counterion for a positively charged nitrogen atom common to all three inhibitors. These results provide a structural basis for understanding how specific antagonists interact with CCR5, and may be useful for the rational design of new, improved CCR5 ligands.


Subject(s)
HIV Fusion Inhibitors/metabolism , Receptors, CCR5/metabolism , Amides/metabolism , Binding Sites/genetics , Cell Line , Cyclic N-Oxides/metabolism , HIV-1/growth & development , Humans , Models, Molecular , Molecular Structure , Mutagenesis, Site-Directed , Oximes , Piperidines/metabolism , Protein Structure, Secondary , Pyridines/metabolism , Quaternary Ammonium Compounds/metabolism , Receptors, CCR5/genetics
5.
Arthritis Rheum ; 52(2): 627-36, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15693002

ABSTRACT

OBJECTIVE: Collagen-induced arthritis (CIA) in the rhesus monkey is a nonhuman primate model of rheumatoid arthritis (RA). The close phylogenetic relationship between humans and the rhesus monkey makes this model useful for the preclinical safety and efficacy testing of new therapies that are inactive in animals more distinctly related to humans. In this study, we tested the therapeutic potential of a novel, small molecular weight antagonist of CCR5, SCH-X, in this model. METHODS: CIA was induced in 10 rhesus monkeys. The animals were allocated to receive SCH-X or saline as the control (n = 5 in each group). Treatment was initiated on the day of CIA induction and continued for 45 days. Monkeys were monitored before and 63 days after CIA induction for macroscopic signs of clinical arthritis, such as soft-tissue swelling and body weight. Furthermore, markers of inflammation and joint degradation were monitored to follow the disease course. RESULTS: Only 2 of 5 animals in the SCH-X-treated group displayed prominent soft-tissue swelling, compared with all 5 saline-treated monkeys. In addition to the suppression of joint inflammation, treatment with SCH-X resulted in a reduction in joint destruction, as demonstrated by lower rates of urinary excretion of collagen crosslinks, with confirmation by histology. Whereas in all saline-treated monkeys, marked erosion of joint cartilage was observed, this was absent in 4 of the 5 SCH-X-treated monkeys. CONCLUSION: The systemic effects of treatment with SCH-X were a suppressed acute-phase reaction (reduction in C-reactive protein level) in the 3 treated monkeys with CIA that remained asymptomatic, and an altered antibody response toward type II collagen. The results suggest that the CCR5 antagonist SCH-X might have a strong clinical potential for treatment during periods of active inflammation, as seen in RA.


Subject(s)
Arthritis, Experimental/prevention & control , CCR5 Receptor Antagonists , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/pathology , Cartilage, Articular/pathology , Collagen Type II , Follow-Up Studies , Macaca mulatta , Male
6.
Bioorg Med Chem Lett ; 15(5): 1375-8, 2005 Mar 01.
Article in English | MEDLINE | ID: mdl-15713390

ABSTRACT

Bipiperidine amide 1 has been identified as a CC chemokine receptor 3 (CCR3) antagonist. Optimization of its structure-activity relationship has resulted in the identification of cis (R,R)-4-[(3,4-dichlorophenyl)methyl]-3-hydroxymethyl-1'(6-quinolinylcarbonyl)-1,4'-bipiperidine 14n, which exhibits potent receptor affinity and inhibition of both calcium flux and eosinophil chemotaxis.


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Animals , Humans , Molecular Structure , Receptors, CCR3 , Structure-Activity Relationship
7.
J Med Chem ; 47(10): 2405-8, 2004 May 06.
Article in English | MEDLINE | ID: mdl-15115380

ABSTRACT

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.


Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , HIV-1/drug effects , Piperazines/chemical synthesis , Piperidines/chemical synthesis , Potassium Channels, Voltage-Gated , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Anti-HIV Agents/adverse effects , Anti-HIV Agents/pharmacology , Biological Availability , Brain/drug effects , Cation Transport Proteins/drug effects , Digestive System/drug effects , Ether-A-Go-Go Potassium Channels , HIV-1/isolation & purification , Humans , In Vitro Techniques , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Macaca fascicularis , Piperazines/adverse effects , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Potassium Channels/drug effects , Pyrimidines/adverse effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship
9.
J Virol ; 77(9): 5201-8, 2003 May.
Article in English | MEDLINE | ID: mdl-12692222

ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) entry is mediated by the consecutive interaction of the envelope glycoprotein gp120 with CD4 and a coreceptor such as CCR5 or CXCR4. The CCR5 coreceptor is used by the most commonly transmitted HIV-1 strains that often persist throughout the course of infection. Compounds targeting CCR5-mediated entry are a novel class of drugs being developed to treat HIV-1 infection. In this study, we have identified the mechanism of action of two inhibitors of CCR5 function, SCH-350581 (AD101) and SCH-351125 (SCH-C). AD101 is more potent than SCH-C at inhibiting HIV-1 replication in primary lymphocytes, as well as viral entry and gp120 binding to cell lines. Both molecules also block the binding of several anti-CCR5 monoclonal antibodies that recognize epitopes in the second extracellular loop of CCR5. Alanine mutagenesis of the transmembrane domain of CCR5 suggests that AD101 and SCH-C bind to overlapping but nonidentical sites within a putative ligand-binding cavity formed by transmembrane helices 1, 2, 3, and 7. We propose that the binding of small molecules to the transmembrane domain of CCR5 may disrupt the conformation of its extracellular domain, thereby inhibiting ligand binding to CCR5.


Subject(s)
CCR5 Receptor Antagonists , Cyclic N-Oxides/pharmacology , HIV-1/drug effects , HIV-1/pathogenicity , Piperidines , Pyridines/pharmacology , Amino Acid Sequence , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , CD4-Positive T-Lymphocytes/virology , Cells, Cultured , HIV Envelope Protein gp120/metabolism , Humans , Membrane Fusion , Models, Molecular , Molecular Sequence Data , Oximes , Pyridines/chemistry , Receptors, CCR5/chemistry , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Virus Replication
12.
Bioorg Med Chem Lett ; 12(23): 3479-82, 2002 Dec 02.
Article in English | MEDLINE | ID: mdl-12419388

ABSTRACT

We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.


Subject(s)
Benzamides/chemistry , Benzylidene Compounds/chemistry , Benzylidene Compounds/pharmacokinetics , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Acetylcholine/analysis , Acetylcholine/biosynthesis , Animals , Area Under Curve , Benzamides/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Microdialysis , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats , Receptors, Muscarinic/metabolism , Structure-Activity Relationship
13.
J Org Chem ; 67(4): 1171-7, 2002 Feb 22.
Article in English | MEDLINE | ID: mdl-11846659

ABSTRACT

Aryl carboxamides are useful structural units found in several biologically active compounds. Unlike their benzoic acid counterparts, fluorinated versions of naphthoic acids are relatively unknown. In connection with a recent project, we needed viable syntheses of several mono- and difluorinated naphthoic acids. Herein we describe the synthesis of 5-, 6-, 7-, and 8-fluoro-1-naphthalenecarboxylic acids and 5,7-, 5,8-, 6,7-, and 4,5-difluoro-1-naphthalenecarboxylic acids. The 5-fluoro derivative 1was obtained from the corresponding 5-bromo compound via electrophilic fluorination of the lithio-intermediate. The rest of the monofluoro (2, 3, and 4) and the difluoro acids (5, 6, and 7) were prepared by a new, general route which entailed the elaboration of commercial fluorinated phenylacetic acids to 2-(fluoroaryl)glutaric acids with differential ester groups; selective hydrolysis to a mono acid, intramolecular Friedel-Crafts cyclization, and aromatization furnished the target structures. An alternative process to assemble a naphthalene skeleton is also presented for the difluoro acids 5 and 6. Finally, 4,5-difluoro-1-naphthalenecarboxylic acid (8) was prepared expeditiously from 1,8-diaminonaphthalene by adapting classical reactions.

14.
Bioorg Med Chem Lett ; 12(5): 795-8, 2002 Mar 11.
Article in English | MEDLINE | ID: mdl-11859005

ABSTRACT

The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.


Subject(s)
Piperazines/chemical synthesis , Piperazines/metabolism , Receptors, Muscarinic/metabolism , Binding Sites , Ligands , Molecular Structure , Piperazines/chemistry , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 12(5): 791-4, 2002 Mar 11.
Article in English | MEDLINE | ID: mdl-11859004

ABSTRACT

A novel series of 2-(R)-methyl-substituted piperazines (e.g., 2) is described. They are potent M(2) selective ligands that have >100-fold selectivity versus the M(1) receptor. In the rat microdialysis assay, compound 14 showed significantly enchanced levels of acetylcholine after oral administration.


Subject(s)
Piperazines/chemical synthesis , Piperazines/metabolism , Receptors, Muscarinic/metabolism , Acetylcholine/metabolism , Administration, Oral , Animals , Binding Sites , Ligands , Microdialysis , Molecular Structure , Piperazines/chemistry , Rats , Receptor, Muscarinic M1 , Receptor, Muscarinic M2
16.
Proc Natl Acad Sci U S A ; 99(1): 395-400, 2002 Jan 08.
Article in English | MEDLINE | ID: mdl-11782552

ABSTRACT

To study HIV-1 escape from a coreceptor antagonist, the R5 primary isolate CC1/85 was passaged in peripheral blood mononuclear cells with increasing concentrations of the CCR5-specific small molecule inhibitor, AD101. By 19 passages, an escape mutant emerged with a >20,000-fold resistance to AD101. This virus was cross-resistant to a related inhibitor, SCH-C, and partially resistant to RANTES but still sensitive to CCR5-specific mAbs. The resistant phenotype was stable; the mutant virus retained AD101 resistance during nine additional passages of culture in the absence of inhibitor. Replication of the escape mutant in peripheral blood mononuclear cells completely depended on CCR5 expression and did not occur in cells from CCR5-Delta32 homozygous individuals. The escape mutant was unable to use CXCR4 or any other tested coreceptor to enter transfected cells. Acquisition of CXCR4 use is not the dominant in vitro escape pathway for a small molecule CCR5 entry inhibitor. Instead, HIV-1 acquires the ability to use CCR5 despite the inhibitor, first by requiring lower levels of CCR5 for entry and then probably by using the drug-bound form of the receptor.


Subject(s)
CCR5 Receptor Antagonists , HIV-1/metabolism , Niacinamide/analogs & derivatives , Piperazines/metabolism , Receptors, CXCR4/metabolism , Amino Acid Sequence , Antibodies, Monoclonal/metabolism , Cells, Cultured , Chemokine CCL5/metabolism , Dose-Response Relationship, Drug , HIV Infections/metabolism , HIV-1/genetics , HIV-1/physiology , HeLa Cells , Humans , Leukocytes, Mononuclear/virology , Molecular Sequence Data , Mutation , Niacinamide/metabolism , Phenotype , Transfection
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