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Publications (19)60.24 Total impact

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    ABSTRACT: Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38alpha MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.
    Bioorganic & medicinal chemistry letters 02/2010; 20(3):828-31. DOI:10.1016/j.bmcl.2009.12.091 · 2.33 Impact Factor
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    ABSTRACT: The design and synthesis of a new class of p38alpha MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38alpha enzymatic and cell-based cytokine TNFalpha production inhibition assays. The optimal linkers between the piperidine and the oxalyl amide were found to be [6,5] fused ring heterocycles. Substituted indoles and azaindoles were favored structural motifs in the cellular assay.
    Bioorganic & medicinal chemistry letters 02/2010; 20(3):1059-62. DOI:10.1016/j.bmcl.2009.12.031 · 2.33 Impact Factor
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    ABSTRACT: A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin-dependant kinase. Inhibitory activities against the enzyme ranged from 34nM to >20microM and were dependant upon both the nature of the aryl group and the tether joining the basic amine to the indolyl maleimide core. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.
    Bioorganic & medicinal chemistry letters 05/2008; 18(7):2395-8. DOI:10.1016/j.bmcl.2008.02.058 · 2.33 Impact Factor
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    ABSTRACT: A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 34nM to >20microM and were dependant upon both the nature of the aryl group and the hydrogen bond donating potential of the maleimide ring. Key interactions with the kinase ATP site and hinge region were found to be consistent with homology modeling predictions.
    Bioorganic & medicinal chemistry letters 05/2008; 18(7):2390-4. DOI:10.1016/j.bmcl.2008.02.059 · 2.33 Impact Factor
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    ABSTRACT: Non-ATP competitive pyrimidine-based inhibitors of CaMKIIdelta were identified. Computational studies were enlisted to predict the probable mode of binding. The results of the computational studies led to the design of ATP competitive inhibitors with optimized hinge interactions. Inhibitors of this class possessed improved enzyme and cellular activity compared to early leads.
    Bioorganic & medicinal chemistry letters 05/2008; 18(7):2404-8. DOI:10.1016/j.bmcl.2008.02.056 · 2.33 Impact Factor
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    ABSTRACT: A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 10nM to >20microM and were dependant upon both the nature of the aryl group and the tether joining the basic amine to the indolyl maleimide core of the inhibitors. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.
    Bioorganic & medicinal chemistry letters 04/2008; 18(7):2399-403. DOI:10.1016/j.bmcl.2008.02.057 · 2.33 Impact Factor
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    ABSTRACT: The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation.
    Pharmacology 02/2008; 81(3):204-20. DOI:10.1159/000112865 · 1.58 Impact Factor
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    ABSTRACT: Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that function within T cells in both normal and stress-related pathophysiological states, including type 1 diabetes. The nonobese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type 1 diabetes in humans. Because p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38alpha MAPK-selective inhibitor, indole-5-carboxamide (SD-169), on the development and progression of type 1 diabetes in the NOD mouse. In preventive treatment studies, SD-169 significantly reduced p38 and HSP60 expression in T cells of the pancreatic beta islets. Following treatment, the incidence of diabetes as determined by blood glucose levels was significantly lower, and immuno-histochemistry of pancreatic beta islet tissue demonstrated significant reduction in CD5+ T cell infiltration in the SD-169 treatment group as compared with untreated NOD mice. In therapeutic studies using mildly and moderately hyperglycemic NOD mice, SD-169 treatment lowered blood glucose and improved glucose homeostasis. Furthermore, following cessation of SD-169 treatment, NOD mice showed significant arrest of diabetes. In conclusion, we report that this p38alpha-selective inhibitor prevents the development and progression of diabetes in NOD mice by inhibiting T cell infiltration and activation, thereby preserving beta cell mass via inhibition of the p38 MAPK signaling pathway. These results have bearing on current prophylactic and therapeutic protocols using p38alpha-selective inhibitors in the prediabetic period for children at high risk of type 1 diabetes, in the honeymoon period, and for adults with latent autoimmune diabetes.
    Journal of Pharmacology and Experimental Therapeutics 08/2006; 318(1):99-107. DOI:10.1124/jpet.105.097857 · 3.86 Impact Factor
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    ABSTRACT: Inhibition of p38 kinase blocks the production of tumor-promoting factors in the multiple myeloma (MM) bone marrow microenvironment. Proteasome inhibitors MG132 and bortezomib have been shown to have direct cytotoxic effects on MM cells. We show that a selective inhibitor of p38alpha, SCIO-469, enhances the ability of MG132 and bortezomib to induce the apoptosis of MM cells. Previously, we showed that p38 inhibition with SCIO-469 enhances MM cytotoxicity of bortezomib by inhibiting the transient expression and phosphorylation of Hsp27, a downstream target of p38. Here we show that continued treatment of MM cells with bortezomib leads to a SCIO-469-enhanced downregulation of Hsp27 and to increased MM apoptosis. Furthermore, we show that p38 inhibition enhances the bortezomib-induced MM apoptosis by upregulation of p53 and downregulation of Bcl-X(L) and Mcl-1. In a mouse xenograft plasmacytoma model of MM, we found that inhibiting p38 augments the effects of bortezomib in decreasing MM tumor growth in vivo. Thus, in addition to its role in suppressing an activated MM microenvironment, co-treatment with a p38 inhibitor, such as SCIO-469, may enhance the cytotoxicity of bortezomib by modulating pro-apoptotic and anti-apoptotic factors in MM cells, suggesting great potential for co-therapy.
    Leukemia 07/2006; 20(6):1017-27. DOI:10.1038/sj.leu.2404200 · 9.38 Impact Factor
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    ABSTRACT: p38alpha Mitogen Activated Protein Kinase (MAP kinase) is an intracellular soluble serine threonine kinase. p38alpha kinase is activated in response to cellular stresses, growth factors and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). The central role of p38alpha activation in settings of both chronic and acute inflammation has led efforts to find inhibitors of this enzyme as possible therapies for diseases such as rheumatoid arthritis, where p38alpha activation is thought to play a causal role. Herein, we report structure-activity relationship studies on a series of indole-based heterocyclic inhibitors that led to the design and identification of a new class of p38alpha inhibitors.
    Bioorganic & Medicinal Chemistry Letters 10/2003; 13(18):3087-90. DOI:10.1016/S0960-894X(03)00653-X · 2.33 Impact Factor
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    ABSTRACT: This study investigates the antinociceptive and the oedema inhibition properties of the novel non-peptide bradykinin (BK) B2 receptor antagonist, NPC 18884. Given by i.p. or p.o. routes NPC 18884 produced graded and long-lasting (at least 2.5h and 5.0h, respectively, for i.p. and p.o. administration) inhibition of acetic acid-induced abdominal constrictions in mice, with mean ID50 values of 8.3 nmol/kg and 439.9 nmol/kg. NPC 18884 also inhibited kaolin-induced abdominal constrictions (44+/-9% and 48+/-3% of inhibition, for i.p. and p.o. routes, respectively). Given by i.p. or p.o. routes NPC 18884 attenuated both phases of formalin-induced licking, as well as formalin-induced oedema formation. At similar doses NPC 18884 produced significant inhibition of capsaicin-induced nociception. NPC 18884, like HOE 140 given i.p., prevented the nociception caused by BK with mean ID50 values of 0.85 nmol/kg and 0.44 nmol/kg, respectively. Given orally NPC 18884, but not HOE 140, caused graded inhibition of BK-induced nociception (mean ID50 value of 50 nmol/kg). In rats, NPC 18884 given i.p. prevented BK and carrageenan-induced hyperalgesia (mean ID50 values of 6 nmol/kg and 13 nmol/kg), without affecting the hyperalgesia induced by des-Arg9-bradykinin (DABK) or by prostaglandin E2 (PGE2). NPC 18884 given i.p. inhibited the mouse paw oedema induced by tyrosine8-bradykinin or by carrageenan, but had no effect on DABK-induced oedema in mice pre-treated with Escherichia coli endotoxin, or that induced by PGE2. Thus, the novel non-peptide BK B2 receptor antagonist NPC 18884 produces rapid onset, potent and relatively long-lasting oral antinociceptive and oedema inhibition properties. The anti-BK actions of NPC 18884 are quite selective towards the BK B2 receptor-mediated responses.
    Archiv für Experimentelle Pathologie und Pharmakologie 10/1999; 360(3):278-86. DOI:10.1007/s002109900080 · 2.36 Impact Factor
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    ABSTRACT: In an effort to rapidly identify potent inhibitors of Abeta production and to probe the amino acid sequence specificity of the protease(s) responsible for the production of this peptide, a large number of dipeptide aldehydes were combinatorially synthesized and manually evaluated for their inhibitory properties. The starting point for this study was the dipeptide aldehyde carbobenzoxyl-valinyl-phenylalanal previously shown to inhibit the production of Abeta in CHO cells stably transfected with the cDNA encoding betaAPP695. Pools of related dipeptide aldehydes were combinatorially synthesized, and the most active pool was deconvoluted, resulting in the identification of the most active inhibitor of this pool. Systematic optimization of this inhibitor resulted in a series of dipeptide aldehydes with enhanced potencies relative to carbobenzoxyl-valinyl-phenylalanal. The most active dipeptide aldehydes were those that possessed hydrophobic amino acids at both the P1 and P2 positions. The most potent compound identified in this study was 3, 5-dimethoxycinnamamide-isoleucinyl-leucinal with an IC(50) of 9.6 microM, approximately 10-fold more active than carbobenzoxyl-valinyl-phenylalanal. In immunoprecipitation experiments using antibodies directed toward either Abeta1-40 or Abeta1-42, 3,5-dimethoxycinnamamide-isoleucinyl-leucinal, like carbobenzoxyl-valinyl-phenylalanal, preferentially inhibited the shorter 1-40 form of Abeta, whereas the longer 1-42 form was not as strongly inhibited. These results suggest that dipeptide aldehydes related to carbobenzoxyl-valinyl-phenylalanal inhibit Abeta through similar mechanisms and demonstrate the utility of a combinatorial synthesis approach to rapidly identify potent inhibitors of Abeta production.
    Journal of Medicinal Chemistry 10/1999; 42(19):3889-98. · 5.48 Impact Factor
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    ABSTRACT: In an effort to rapidly identify potent inhibitors of Aβ production and to probe the amino acid sequence specificity of the protease(s) responsible for the production of this peptide, a large number of dipeptide aldehydes were combinatorially synthesized and manually evaluated for their inhibitory properties. The starting point for this study was the dipeptide aldehyde carbobenzoxyl-valinyl-phenylalanal previously shown to inhibit the production of Aβ in CHO cells stably transfected with the cDNA encoding βAPP695. Pools of related dipeptide aldehydes were combinatorially synthesized, and the most active pool was deconvoluted, resulting in the identification of the most active inhibitor of this pool. Systematic optimization of this inhibitor resulted in a series of dipeptide aldehydes with enhanced potencies relative to carbobenzoxyl-valinyl-phenylalanal. The most active dipeptide aldehydes were those that possessed hydrophobic amino acids at both the P1 and P2 positions. The most potent compound identified in this study was 3,5-dimethoxycinnamamide-isoleucinyl-leucinal with an IC50 of 9.6 μM, approximately 10-fold more active than carbobenzoxyl-valinyl-phenylalanal. In immunoprecipitation experiments using antibodies directed toward either Aβ1−40 or Aβ1−42, 3,5-dimethoxycinnamamide-isoleucinyl-leucinal, like carbobenzoxyl-valinyl-phenylalanal, preferentially inhibited the shorter 1−40 form of Aβ, whereas the longer 1−42 form was not as strongly inhibited. These results suggest that dipeptide aldehydes related to carbobenzoxyl-valinyl-phenylalanal inhibit Aβ through similar mechanisms and demonstrate the utility of a combinatorial synthesis approach to rapidly identify potent inhibitors of Aβ production.
    Journal of Medicinal Chemistry 08/1999; 42(19). DOI:10.1021/jm990009f · 5.48 Impact Factor
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    ABSTRACT: This study describes the anti-inflammatory actions of NPC 18884, a non-peptide bradykinin B2 receptor antagonist in bradykinin and carrageenan-induced inflammation in the mouse model of pleurisy. The selectivity of NPC 18884 was assessed in the pleurisy caused by histamine, substance P and des-Arg9-bradykinin. NPC 18884 given intraperitoneally or orally inhibited bradykinin-induced leukocytes influx (ID50 value of 63 nmol/kg and 141 nmol/kg, respectively). The NPC 18884 also inhibited the exudation induced by bradykinin (P < 0.05). NPC 18884 given either intraperitoneally or orally caused dose-dependent inhibition of the exudation and total and differential cell content caused by intrapleural injection of carrageenan (1%, assessed 4 h after), with mean ID50, values of 132 and 295 nmol/kg, respectively. The NPC 18884 actions installs rapidly (0.5 h), lasted for up to 4 h and were selective for the bradykinin B2 receptors; at similar doses it had no significant effect against the inflammatory responses induced by des-Arg9-bradykinin, histamine or substance P. These results indicate that the novel non-peptide bradykinin B2 receptor antagonist, NPC 18884, exhibited selective intraperitoneal and oral anti-inflammatory properties when assessed in the inflammatory reaction induced by bradykinin and carrageenan in the mice model of pleurisy.
    European Journal of Pharmacology 12/1998; 363(2-3):179-87. DOI:10.1016/S0014-2999(98)00778-X · 2.68 Impact Factor
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    ABSTRACT: A simple and general approach to the synthesis of chemical libraries based on a universal anhydride template allows the preparation of large number of compounds. Various cyclic/acyclic amines, primary/secondary amines, differentially protected bifunctional amines were used as nucleophiles to react with anhydrides. The free carboxylic acid generated was then coupled with solid-bound amines. The facile and rapid generation of compounds through this multi-component assembly can be accomplished in a combinatorial parallel synthesis.
    Molecular Diversity 05/1997; 3(2):121-8. DOI:10.1023/A:1009662605993 · 2.54 Impact Factor
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    ABSTRACT: The novel pseudopeptide bradykinin B2 receptor antagonist containing the 1,3,8-triazaspiro[4,5]decan-4-one ring system, NPC 18521 (D-Arg-Arg-[1,3-phenyl,8-triazaspiro[4,5]-decane-4-one-3-acetyl]-S er-D -tetrahydroisoquinolinyl-octahydroindolinyl-Arg) (10 and 30 nmol/kg, i.p.), given 30 min prior, produced significant and long-lasting inhibition of rat paw oedema induced by bradykinin (3 nmol/paw) and carrageenan (300 micrograms/paw), without affecting the oedema induced by the selective bradykinin B1 receptor agonist, des-Arg9-bradykinin, in rats pretreated with Escherichia coli endotoxin. In contrast, when injected locally into the rat or mouse hindpaw, NPC 18521 (1-100 nmol) elicited dose-related oedema formation. This effect was almost completely blocked by cyproheptadine (20 mg/kg, i.p.) or by compound 48/80 (12 micrograms/paw), but was unaffected by Hoe 140 (D-Arg-[Hyp5,Thi5,Tic7,Oic8]bradykinin). NPC 18521 (0.3-10 nmol/kg, i.p.) produced significant inhibition of acetic acid, acetylcholine and kaolin- but not zymosan-induced abdominal constrictions in mice. The calculated mean ID50 values for these effects were 0.84, 0.46 and 0.55 nmol/kg, respectively. The antinociceptive action of NPC 18521 (3 nmol/kg, i.p.) had a rapid onset (15 min) and lasted for up to 120 min. Given topically (0.01-0.3 nmol), NPC 18521 produced significant attenuation of both the early and the late phase of the formalin-induced licking, as well as formalin-induced oedema formation. In addition, NPC 18521 given both systemically or topically, produced significant inhibition of the neurogenic nociception caused by topical injection of capsaicin. Given topically in the rat paw, NPC 18521 (10 nmol) caused marked hyperalgesia, an effect which was completely prevented by cyproheptadine (20 mg/kg, i.p.), but was unaffected by Hoe 140 (3 nmol/kg, i.p.). Given intraperitoneally, 30 min prior, NPC 18521 (3-30 nmol/kg) like Hoe 140 (1-10 nmol/kg) prevented, in a dose-dependent manner, bradykinin (3 nmol/paw)-induced hyperalgesia with mean ID50 values of 13.16 and 1.36 nmol/kg, respectively. Thus, the novel pseudopeptide bradykinin B2 receptor antagonist, NPC 18521, has an effect with rapid onset, and produces potent and relatively long-lasting antioedematogenic and antinociceptive properties. However, in contrast to Hoe 140, given locally into the hindpaw, NPC 18521 elicited marked oedema formation and hyperalgesia, an effect which seems to be secondary to mast cell degranulation and histamine and/or serotonin release. Finally, the anti-bradykinin actions of NPC 18521 are quite selective towards the bradykinin B2 receptor-mediated responses.
    European Journal of Pharmacology 01/1997; 316(2-3):277-86. DOI:10.1016/S0014-2999(96)00661-9 · 2.68 Impact Factor
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    ABSTRACT: A series of pseudopeptides containing alkyl-, cycloalkyl-, aryl-, and aralkyl-substituted 1,3,8-triazaspiro[4.5]decan-4-one-3-acetic acids as amino acid surrogates to replace the Pro2-Pro3-Gly4-Phe5 section of the peptide bradykinin B2 receptor antagonist [Pro3, Phe5]HOE 140 (D-Arg0-Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-D-Tic7+ ++-Oic8-Arg9) were prepared. These psuedopeptides were examined in vitro for their B2 receptor affinities as well as for their ability to block bradykinin mediated actions in vivo. Two compounds in particular, NPC 18521 (I) and NPC 18688 (V) were quite potent in these latter assays, indicating that a significant portion of this prototypical second generation decapeptide antagonist can be replaced with a more compact nonpeptide molecule.
    Journal of Medicinal Chemistry 09/1996; 39(16):3169-73. DOI:10.1021/jm950676i · 5.48 Impact Factor
  • Immunopharmacology 07/1996; 33(1-3):61-7. DOI:10.1016/0162-3109(96)00057-4
  • Babu J. Mavunkel · Zhijian Lu · Donald J. Kyle
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    ABSTRACT: Novel and efficient syntheses have been developed for the (R)-and (S)- enantiomers of a series of phenylalanine homologues.
    Tetrahedron Letters 04/1993; 34(14):2255-2258. DOI:10.1016/S0040-4039(00)77587-3 · 2.39 Impact Factor