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1.
J Med Chem ; 51(19): 5958-63, 2008 Oct 09.
Article in English | MEDLINE | ID: mdl-18783200

ABSTRACT

The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCtheta) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCtheta enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCtheta high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5-(3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low microM ATP competitive PKCtheta inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3-pyridinecarbonitrile 4p, a 70 nM PKCtheta inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCbeta, and PKCzeta, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.


Subject(s)
Indoles/pharmacology , Isoenzymes/antagonists & inhibitors , Nitriles/pharmacology , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Indoles/chemical synthesis , Indoles/chemistry , Interleukin-2/antagonists & inhibitors , Interleukin-2/biosynthesis , Isoenzymes/deficiency , Isoenzymes/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , Molecular Structure , Nitriles/chemical synthesis , Nitriles/chemistry , Protein Kinase C/deficiency , Protein Kinase C/drug effects , Protein Kinase C-theta , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Stereoisomerism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
2.
J Med Chem ; 50(23): 5535-8, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17948978

ABSTRACT

N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.


Subject(s)
Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemical synthesis , Thiazoles/chemistry , Tryptamines/chemical synthesis , Administration, Oral , Animals , Biological Availability , CHO Cells , Cricetinae , Cricetulus , Dogs , Frontal Lobe/metabolism , Haplorhini , Humans , In Vitro Techniques , Mice , Microdialysis , Microsomes, Liver/metabolism , Radioligand Assay , Rats , Serotonin Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/pharmacology , Solubility , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Tryptamines/chemistry , Tryptamines/pharmacokinetics , Tryptamines/pharmacology , gamma-Aminobutyric Acid/metabolism
3.
J Comb Chem ; 6(1): 78-82, 2004.
Article in English | MEDLINE | ID: mdl-14714988

ABSTRACT

This paper describes an investigation into decreasing the run time for high-throughput semipreparative RP-HPLC methods without compromising the resolution. Experimental design was used to devise a small set of experiments in which factors, including solvent flow rate, solvent/column temperature, at-column dilution, and run time were varied systematically. The results were analyzed by means of multiple regression and partial least squares to generate a model relating the factors to the results, showing which factors are important. The model was then used to determine the optimal conditions.

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