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1.
J Biomol Screen ; 17(7): 857-67, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22584786

ABSTRACT

Development of inhibitor compounds selective against undesirable targets is critical in drug discovery. Selectivity ratios for candidate compounds are evaluated by dividing potencies from two assays assessing the off-target and target. Because all potency measurements have underlying uncertainty, understanding error propagation is essential to interpreting selectivity data. Assay noise introduces ambiguity in the statistical significance of selectivity ratios, particularly at low replicate numbers when compounds are often prioritized for subsequent testing. The ability to differentiate potency results for any pair of compounds in one assay is evaluated using a metric called minimum significant ratio (MSR). Potency results of one compound tested in a pair of assays can be differentiated by the minimum significant selectivity ratio (MSSR). To differentiate selectivity ratios for any pair of compounds, we extend this concept by proposing two new parameters called the minimum significant ratio of selectivity ratios (MSRSR) and confidence in ratio of selectivity ratios (CRSR). Importantly, these tools can be used after a single selectivity measurement. We describe these methods and illustrate their usefulness using structure-activity relationship data from a Janus kinase inhibitor project, in which these tools informed a cogent retesting strategy and enabled rapid and objective decision making.


Subject(s)
Drug Discovery , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Pharmaceutical Preparations/analysis , Cell Physiological Phenomena , Data Interpretation, Statistical , Enzyme Inhibitors/chemistry , Janus Kinases/metabolism , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 18(4): 1318-22, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18242983

ABSTRACT

Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.


Subject(s)
Cyclobutanes/chemistry , Cyclobutanes/pharmacology , Diamines/chemistry , Diamines/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Cell Line , Cyclobutanes/chemical synthesis , Diamines/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Mice , Stereoisomerism , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 18(1): 228-31, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18006311

ABSTRACT

A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-alpha and IL-8 mediated in vitro hPMN MPO release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed SAR has been discussed in these two closely related structures.


Subject(s)
Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Chemokine CXCL1/chemistry , Chemokine CXCL1/pharmacology , Chemotactic Factors/chemistry , Chemotactic Factors/pharmacology , Humans , Interleukin-8/chemistry , Interleukin-8/pharmacology , Kinetics , Neutrophils/drug effects , Neutrophils/enzymology , Oxides/chemical synthesis , Oxides/chemistry , Oxides/pharmacokinetics , Oxides/pharmacology , Peroxidase/metabolism , Rats , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiadiazoles/pharmacokinetics , Thiadiazoles/pharmacology
4.
J Pharmacol Exp Ther ; 322(2): 477-85, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17496166

ABSTRACT

In neutrophils, growth-related protein-alpha (CXCL1) and interleukin-8 (CXCL8), are potent chemoattractants (Cytokine 14:27-36, 2001; Biochemistry 42:2874-2886, 2003) and can stimulate myeloperoxidase release via activation of the G protein-coupled receptors CXCR1 and CXCR2. The role of CXCR1 and CXCR2 in the pathogenesis of inflammatory responses has encouraged the development of small molecule antagonists for these receptors. The data presented herein describe the pharmacology of 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (Sch527123), a novel antagonist of both CXCR1 and CXCR2. Sch527123 inhibited chemokine binding to (and activation of) these receptors in an insurmountable manner and, as such, is categorized as an allosteric antagonist. Sch527123 inhibited neutrophil chemotaxis and myeloperoxidase release in response to CXCL1 and CXCL8 but had no effect on the response of these cells to C5a or formyl-methionyl-leucyl-phenylalanine. The pharmacological specificity of Sch527123 was confirmed by testing in a diversity profile against a panel of enzymes, channels, and receptors. To measure compound affinity, we characterized [(3)H]Sch527123 in both equilibrium and nonequilibrium binding analyses. Sch527123 binding to CXCR1 and CXCR2 was both saturable and reversible. Although Sch527123 bound to CXCR1 with good affinity (K(d) = 3.9 +/- 0.3 nM), the compound is CXCR2-selective (K(d) = 0.049 +/- 0.004 nM). Taken together, our data show that Sch527123 represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.


Subject(s)
Benzamides/pharmacology , Cyclobutanes/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Benzamides/chemistry , Binding, Competitive/drug effects , Calcium Signaling/drug effects , Cell Line , Cell Membrane/metabolism , Chemotaxis/drug effects , Complement C5a/pharmacology , Cyclobutanes/chemistry , Dose-Response Relationship, Drug , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Interleukin-8/metabolism , Mice , Molecular Structure , N-Formylmethionine Leucyl-Phenylalanine/pharmacology , Neutrophils/cytology , Neutrophils/drug effects , Protein Binding/drug effects , Radioligand Assay , Receptors, Interleukin-8A/genetics , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/genetics , Receptors, Interleukin-8B/metabolism , Signal Transduction/drug effects
5.
Bioorg Med Chem Lett ; 17(13): 3778-83, 2007 Jul 01.
Article in English | MEDLINE | ID: mdl-17459706

ABSTRACT

A novel series of cyclobutenedione centered C(4)-alkyl substituted furanyl analogs was developed as potent CXCR2 and CXCR1 antagonists. Compound 16 exhibits potent inhibitory activities against IL-8 binding to the receptors (CXCR2 Ki=1 nM, IC(50)=1.3 nM; CXCR1 Ki=3 nM, IC(50)=7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5 nM, CXCR1 IC(50)=37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog.


Subject(s)
Chemistry, Pharmaceutical/methods , Furans/chemistry , Furans/pharmacokinetics , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Dogs , Drug Design , Furans/chemical synthesis , Humans , Inhibitory Concentration 50 , Interleukin-8/chemistry , Kinetics , Mice , Rats
6.
J Med Chem ; 49(26): 7603-6, 2006 Dec 28.
Article in English | MEDLINE | ID: mdl-17181143

ABSTRACT

Structure-activity studies on lead cyclobutenedione 3 led to the discovery of 4 (SCH 527123), a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist with excellent cell-based activity. Compound 4 displayed good oral bioavailability in rat and may be a potential therapeutic agent for the treatment of various inflammatory diseases.


Subject(s)
Benzamides/pharmacology , Cyclobutanes/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemical synthesis , Biological Availability , Cyclobutanes/administration & dosage , Cyclobutanes/chemical synthesis , Molecular Structure , Rats , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/metabolism , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 15(12): 3020-3, 2005 Jun 15.
Article in English | MEDLINE | ID: mdl-15908209

ABSTRACT

Structure-activity relationship study of bipiperidine amide 1 has identified the reverse bipiperidine amide 4a as a CC chemokine-3 (CCR3) receptor antagonist. Optimization of the structure-activity relationship of compound 4a has resulted in the identification of a CCR3 antagonist 4i as well as a CCR3 agonist 13.


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Chemokine/agonists , Receptors, Chemokine/antagonists & inhibitors , Chemokine CCL11 , Chemokines, CC/metabolism , Chemotactic Factors, Eosinophil/metabolism , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Protein Binding , Receptors, CCR3 , Receptors, HIV/agonists , Receptors, HIV/antagonists & inhibitors , Structure-Activity Relationship
8.
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
9.
Eur J Pharmacol ; 456(1-3): 1-10, 2002 Dec 05.
Article in English | MEDLINE | ID: mdl-12450563

ABSTRACT

Study of the CC chemokine receptor 3 (CCR3) has been limited to using radiolabeled agonist chemokines. A small molecule CCR3 antagonist, 2-[(6-amino-2-benzothiazolyl)thio]-N-[1-[(3,4-dichlorylphenyl)methyl]-4-piperidinyl]acetamide, Banyu (I), was tritiated and used for pharmacological studies. Banyu (I) has a K(d) of 5.0+/-0.4 and 4.3+/-1.8 nM on human CCR3 transfectants and eosinophils, and noncompetitively inhibits [125I]eotaxin binding and eotaxin-induced [35S]guanosine-5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding. The proportion of [125I]eotaxin: [3H]Banyu (I) binding sites in eosinophils or transfectants was 35% or 13%, although both binding sites were overexpressed in transfectants. CCR3 spontaneously couples to G-proteins in CCR3 transfectants, demonstrated by changes in basal and eotaxin-induced [35S]GTPgammaS binding under reduced NaCl and GDP concentrations. Consequently, Banyu (I) was identified as an inverse agonist. In contrast, CCL18 and I-TAC (interferon-inducible T cell alpha-chemoattractant) were neutral antagonists, inhibiting eotaxin-induced [35S]GTPgammaS binding, with minimal effect on basal coupling of CCR3 to G proteins. Eotaxin, eotaxin-2 and monocyte chemoattractant protein (MCP)-4 are full agonists inducing [35S]GTPgammaS binding; eotaxin-3, MCP-3, RANTES (regulated on activation normal T cell expressed and secreted), vMIP-I (Kaposi's sarcoma-associated herpesvirus macrophage inflammatory protein-) and vMIP-II are partial agonists, indicating that this is a sensitive method to quantitate agonist efficacy.


Subject(s)
Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Receptors, Chemokine/agonists , Animals , Binding, Competitive/drug effects , CHO Cells , Cell Line , Cell Membrane/drug effects , Cell Membrane/metabolism , Cells, Cultured , Chemokine CCL11 , Chemokine CCL5/metabolism , Chemokine CCL5/pharmacology , Chemokines/metabolism , Chemokines/pharmacology , Chemokines, CC/metabolism , Chemokines, CC/pharmacology , Cricetinae , Dose-Response Relationship, Drug , Eosinophils/cytology , Eosinophils/drug effects , Eosinophils/metabolism , Humans , Monocyte Chemoattractant Proteins/metabolism , Monocyte Chemoattractant Proteins/pharmacology , Radioligand Assay , Rats , Receptors, CCR3 , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Sulfur Radioisotopes , Transfection
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