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Article: Potential histamine H2-receptor blockers. 3- and 2-indole derivatives as immobile analogues of tautomeric forms of cimetidine.

Tecle, H / Robichaud, L / Schwender, C F

1981 Volume 24, Issue 9, Page(s) 1095–1097

Abstract: At physiological pH, cimetidine (1a) and its analogues burimamide (1b) and metiamide (1c) exist mainly as an equilibrium mixture of tautomers. A high concentration of tautomer 2 is associated with increased H2-receptor interaction. 3-Indole derivatives ( ... ...

Abstract	At physiological pH, cimetidine (1a) and its analogues burimamide (1b) and metiamide (1c) exist mainly as an equilibrium mixture of tautomers. A high concentration of tautomer 2 is associated with increased H2-receptor interaction. 3-Indole derivatives (5c-f) and 2-indole derivatives (6c-f) were synthesized and tested as immobile analogues of tautomers 2 and 3, respectively. Weak competitive H2 antagonism was found in N'-cyano-N-[2-[(1H-indol-3-ylmethyl)thio]ethyl]carbamidothioic acid methyl ester (5e) and N-[2-[(1H-indol-2-ylmethyl)thio]-ethyl]-N'-methylthiourea (6c).
MeSH term(s)	Animals ; Chemical Phenomena ; Chemistry ; Cimetidine/analogs & derivatives ; Cimetidine/chemical synthesis ; Cimetidine/pharmacology ; Guanidines ; Guinea Pigs ; Heart Rate/drug effects ; Histamine H2 Antagonists/chemical synthesis ; Indoles/chemical synthesis ; Indoles/pharmacology ; Male ; Methylhistamines/pharmacology ; Stereoisomerism
Chemical Substances	Guanidines ; Histamine H2 Antagonists ; Indoles ; Methylhistamines ; 4-methylhistamine (54ST71P9EE) ; Cimetidine (80061L1WGD)
Language	English
Publishing date	1981-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm00141a017
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Article: Mutations of aspartate 103 in the Hm2 receptor and alterations in receptor binding properties of muscarinic agonists.

Schwarz, R D / Spencer, C J / Jaen, J C / Mirzadegan, T / Moreland, D / Tecle, H / Thomas, A J

Life sciences

1995 Volume 56, Issue 11-12, Page(s) 923–929

Abstract: Aspartate 103 (D103) in the third transmembrane domain of the Hm2 receptor was mutated to glutamate (D103E), asparagine (D103N), or alanine (D103A). As measured by [3H]-NMS, no significant binding was observed in D103A, while a 2-fold decrease in ligand ... ...

Abstract	Aspartate 103 (D103) in the third transmembrane domain of the Hm2 receptor was mutated to glutamate (D103E), asparagine (D103N), or alanine (D103A). As measured by [3H]-NMS, no significant binding was observed in D103A, while a 2-fold decrease in ligand affinity was seen in D103E and a 32-fold decrease in affinity was found in the D103N mutant. Examination of reference agonists showed greater loss of affinity in D103N than in D103E with the rank order of change being: L-607,207>carbachol>arecoline>pilocarpine>oxotremorine>McN-A-343. Of the novel 1-azabicyclo[2.2.1]-heptan-3-one oxime agonists examined, arylacetylene oximes showed little alteration in binding in either the D103E or D103N mutants, while the geometric isomers of several bicyclic aryl-ene-yne oximes showed significant changes in affinity, especially in the D103N mutant. Thus, overall size of the agonist and/or spatial orientation of the molecule within the binding pocket contribute to changes measured in binding.
MeSH term(s)	(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/metabolism ; (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/pharmacology ; Alanine/genetics ; Amino Acid Substitution ; Animals ; Arecoline/metabolism ; Arecoline/pharmacology ; Asparagine/genetics ; Aspartic Acid/genetics ; COS Cells ; Carbachol/metabolism ; Carbachol/pharmacology ; Muscarinic Agonists/metabolism ; Muscarinic Agonists/pharmacology ; Mutagenesis, Site-Directed ; Oxotremorine/metabolism ; Oxotremorine/pharmacology ; Pilocarpine/metabolism ; Pilocarpine/pharmacology ; Receptor, Muscarinic M2 ; Receptors, Muscarinic/genetics ; Receptors, Muscarinic/metabolism ; Transfection
Chemical Substances	Muscarinic Agonists ; Receptor, Muscarinic M2 ; Receptors, Muscarinic ; Pilocarpine (01MI4Q9DI3) ; Aspartic Acid (30KYC7MIAI) ; Arecoline (4ALN5933BH) ; (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride (55-45-8) ; Oxotremorine (5RY0UWH1JL) ; Asparagine (7006-34-0) ; Carbachol (8Y164V895Y) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	1995
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/0024-3205(95)00029-6
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Article ; Online: Beyond the MEK-pocket: can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK?

Tecle, Haile / Shao, Jianxing / Li, Yanhong / Kothe, Michael / Kazmirski, Steven / Penzotti, Julie / Ding, Yuan-Hua / Ohren, Jeffrey / Moshinsky, Deb / Coli, Rocco / Jhawar, Nidhi / Bora, Emilia / Jacques-O'Hagan, Suzanne / Wu, Joe

Bioorganic & medicinal chemistry letters

2009 Volume 19, Issue 1, Page(s) 226–229

Abstract: An approach and preliminary results for utilizing legacy MEK inhibitors as templates for a reiterative structural based design and synthesis of novel, type III NCKIs (non-classical kinase inhibitors) is described. Evidence is provided that the MEK-pocket ...

Abstract	An approach and preliminary results for utilizing legacy MEK inhibitors as templates for a reiterative structural based design and synthesis of novel, type III NCKIs (non-classical kinase inhibitors) is described. Evidence is provided that the MEK-pocket or pockets closely related to it may exist in kinases other than MEK.
MeSH term(s)	Catalytic Domain ; Drug Design ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology
Chemical Substances	Protein Kinase Inhibitors ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
Language	English
Publishing date	2009-01-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2008.10.108
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Article: Characterization of muscarinic agonists in recombinant cell lines.

Schwarz, R D / Davis, R E / Jaen, J C / Spencer, C J / Tecle, H / Thomas, A J

Life sciences

1993 Volume 52, Issue 5-6, Page(s) 465–472

Abstract: Using recombinant CHO cells that express Hm1-Hm5 receptors, reference muscarinic agonists have been characterized with respect to their activity in receptor binding and second messenger assays. In whole cell [3H]-N-methyl scopolamine binding, no agonist ... ...

Abstract	Using recombinant CHO cells that express Hm1-Hm5 receptors, reference muscarinic agonists have been characterized with respect to their activity in receptor binding and second messenger assays. In whole cell [3H]-N-methyl scopolamine binding, no agonist was found to be truly subtype selective, although some showed marked differences between several of the subtypes (e.g. m1 vs. m2). As a functional index of receptor activation, phosphatidyl-inositol (PI) turnover was measured for m1, m3, and m5 receptors while inhibition of forskolin-stimulated cAMP accumulation was measured for m2 and m4 receptors. Both full and partial agonists were delineated in PI turnover, but all agonists showed similar responses on cAMP. Alkylation studies with propylbenzylcholine mustard showed that both efficacy and potency were markedly affected in the functional assays by the number of free receptors. Thus, receptor reserve appears to play a major role in the determination of subtype selectivity for agonists using functional measures. Even with these limitations, however, the use of transformed cell lines is playing a pivotal role in the discovery of selective agonists.
MeSH term(s)	Animals ; CHO Cells ; Cell Line, Transformed ; Colforsin/pharmacology ; Cricetinae ; Cyclic AMP/metabolism ; N-Methylscopolamine ; Parasympatholytics/metabolism ; Parasympathomimetics/metabolism ; Phosphatidylinositols/metabolism ; Receptors, Muscarinic/metabolism ; Recombination, Genetic ; Scopolamine Derivatives/metabolism
Chemical Substances	Parasympatholytics ; Parasympathomimetics ; Phosphatidylinositols ; Receptors, Muscarinic ; Scopolamine Derivatives ; Colforsin (1F7A44V6OU) ; Cyclic AMP (E0399OZS9N) ; N-Methylscopolamine (VDR09VTQ8U)
Language	English
Publishing date	1993
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/0024-3205(93)90303-k
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Article: Synthesis and SAR of bulky 1-azabicyclo[2.2.1]-3-one oximes as muscarinic receptor subtype selective agonists.

Tecle, H / Lauffer, D J / Mirzadegan, T / Moos, W H / Moreland, D W / Pavia, M R / Schwarz, R D / Davis, R E

Life sciences

1993 Volume 52, Issue 5-6, Page(s) 505–511

Abstract: The synthesis of a series of potent and efficacious 1-azabicyclo[2.2.1]heptan-3-one oxime muscarinic agonists is described. The oximes have extended appendages designed to span the cavity defined by the seven transmembrane helices of the muscarinic ... ...

Abstract	The synthesis of a series of potent and efficacious 1-azabicyclo[2.2.1]heptan-3-one oxime muscarinic agonists is described. The oximes have extended appendages designed to span the cavity defined by the seven transmembrane helices of the muscarinic receptor. Some members of the series are selective for receptors of the m1 subtype. One such oxime, 31, shows affinity and functional selectivity for m1 over m2, m3, and m4 muscarinic receptor types.
MeSH term(s)	Animals ; Bridged Bicyclo Compounds/chemical synthesis ; Bridged Bicyclo Compounds/pharmacology ; CHO Cells ; Cerebral Cortex/drug effects ; Colforsin/pharmacology ; Cricetinae ; Cyclic AMP/metabolism ; Dioxolanes/metabolism ; Inositol Phosphates/metabolism ; Ligands ; Oximes/chemical synthesis ; Oximes/pharmacology ; Parasympathomimetics/chemical synthesis ; Parasympathomimetics/metabolism ; Parasympathomimetics/pharmacology ; Quinuclidinyl Benzilate/metabolism ; Radioligand Assay ; Rats ; Receptors, Muscarinic/drug effects ; Receptors, Muscarinic/metabolism ; Structure-Activity Relationship
Chemical Substances	Bridged Bicyclo Compounds ; Dioxolanes ; Inositol Phosphates ; Ligands ; Oximes ; Parasympathomimetics ; Receptors, Muscarinic ; Colforsin (1F7A44V6OU) ; 2-methyldioxolane (497-26-7) ; Quinuclidinyl Benzilate (6581-06-2) ; Cyclic AMP (E0399OZS9N)
Language	English
Publishing date	1993
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/0024-3205(93)90308-p
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Article ; Online: Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.

Smaill, Jeff B / Gonzales, Andrea J / Spicer, Julie A / Lee, Helen / Reed, Jessica E / Sexton, Karen / Althaus, Irene W / Zhu, Tong / Black, Shannon L / Blaser, Adrian / Denny, William A / Ellis, Paul A / Fakhoury, Stephen / Harvey, Patricia J / Hook, Ken / McCarthy, Florence O J / Palmer, Brian D / Rivault, Freddy / Schlosser, Kevin /

Ellis, Teresa / Thompson, Andrew M / Trachet, Erin / Winters, R Thomas / Tecle, Haile / Bridges, Alexander

Journal of medicinal chemistry

2016 Volume 59, Issue 17, Page(s) 8103–8124

Abstract: Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were ...

Abstract	Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
MeSH term(s)	Administration, Oral ; Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Dogs ; Heterografts ; Humans ; Injections, Intravenous ; Macaca fascicularis ; Male ; Mice, Nude ; Morpholines/chemical synthesis ; Morpholines/chemistry ; Morpholines/pharmacokinetics ; Morpholines/pharmacology ; Neoplasm Transplantation ; Phosphorylation ; Pyridines/chemical synthesis ; Pyridines/chemistry ; Pyridines/pharmacokinetics ; Pyridines/pharmacology ; Pyrimidines/chemical synthesis ; Pyrimidines/chemistry ; Pyrimidines/pharmacokinetics ; Pyrimidines/pharmacology ; Quinazolines/chemical synthesis ; Quinazolines/chemistry ; Quinazolines/pharmacokinetics ; Quinazolines/pharmacology ; Quinazolinones/chemical synthesis ; Quinazolinones/chemistry ; Quinazolinones/pharmacokinetics ; Quinazolinones/pharmacology ; Rats, Sprague-Dawley ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Stereoisomerism ; Structure-Activity Relationship
Chemical Substances	Antineoplastic Agents ; Morpholines ; PF 00299804 ; Pyridines ; Pyrimidines ; Quinazolines ; Quinazolinones ; Canertinib (C78W1K5ASF) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1)
Language	English
Publishing date	2016--08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.6b00883
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Article: Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization.

Schwarz, R D / Callahan, M J / Coughenour, L L / Dickerson, M R / Kinsora, J J / Lipinski, W J / Raby, C A / Spencer, C J / Tecle, H

The Journal of pharmacology and experimental therapeutics

1999 Volume 291, Issue 2, Page(s) 812–822

Abstract: Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. ...

Abstract	Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined at the five subtypes of human muscarinic receptors (hM(1)-hM(5)) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated phosphatidylinositol hydrolysis in hM(1) and hM(3) CHO cells and inhibited forskolin-activated cAMP accumulation in hM(2) and hM(4) CHO cells. Additionally, it decreased K(+)-stimulated release of [(3)H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant binding to approximately 30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal. Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus, milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors.
MeSH term(s)	Acetylcholine/secretion ; Animals ; Behavior, Animal/drug effects ; Binding Sites ; CHO Cells ; Cerebral Cortex/drug effects ; Cholinesterase Inhibitors/pharmacology ; Cognition/drug effects ; Colforsin/metabolism ; Cricetinae ; Cyclic AMP ; Dihydropyridines/pharmacology ; Dose-Response Relationship, Drug ; Electroencephalography/drug effects ; Humans ; In Vitro Techniques ; Macaca mulatta ; Male ; Muscarinic Agonists/pharmacology ; Neurotransmitter Agents/metabolism ; Oximes/pharmacology ; Phosphatidylinositols/metabolism ; Potassium/physiology ; Rats ; Rats, Long-Evans ; Receptors, Muscarinic/drug effects ; Scopolamine Hydrobromide/pharmacology ; Time Factors ; Transfection
Chemical Substances	Cholinesterase Inhibitors ; Dihydropyridines ; Muscarinic Agonists ; Neurotransmitter Agents ; Oximes ; Phosphatidylinositols ; Receptors, Muscarinic ; Colforsin (1F7A44V6OU) ; Scopolamine Hydrobromide (451IFR0GXB) ; Cyclic AMP (E0399OZS9N) ; Acetylcholine (N9YNS0M02X) ; milameline (R9X77R42FN) ; Potassium (RWP5GA015D)
Language	English
Publishing date	1999-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
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Article: Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.

Sebolt-Leopold, J S / Dudley, D T / Herrera, R / Van Becelaere, K / Wiland, A / Gowan, R C / Tecle, H / Barrett, S D / Bridges, A / Przybranowski, S / Leopold, W R / Saltiel, A R

Nature medicine

1999 Volume 5, Issue 7, Page(s) 810–816

Abstract: The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was ... ...

Abstract	The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.
MeSH term(s)	Animals ; Benzamides/pharmacology ; Benzamides/therapeutic use ; Cadherins/analysis ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors ; Cell Cycle/drug effects ; Cell Division/drug effects ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/enzymology ; Colonic Neoplasms/pathology ; Colonic Neoplasms/physiopathology ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Female ; Hepatocyte Growth Factor/pharmacology ; Humans ; Male ; Mice ; Mice, Inbred Strains ; Mice, Nude ; Neoplasm Invasiveness/prevention & control ; Signal Transduction/drug effects ; Transplantation, Heterologous ; Tumor Cells, Cultured
Chemical Substances	2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide ; Benzamides ; Cadherins ; Enzyme Inhibitors ; Hepatocyte Growth Factor (67256-21-7) ; Calcium-Calmodulin-Dependent Protein Kinases (EC 2.7.11.17)
Language	English
Publishing date	1999-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/10533
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Article ; Online: Enhanced selectivity profile of pyrazole-urea based DFG-out p38alpha inhibitors.

Liu, Hu / Kuhn, Cyrille / Feru, Frederic / Jacques, Suzanne L / Deshmukh, Gayatri D / Ye, Ping / Rennie, Glen R / Johnson, Theresa / Kazmirski, Steven / Low, Simon / Coli, Rocco / Ding, Yuan-hua / Cheng, Alan C / Tecle, Haile / English, Jessie M / Stanton, Robert / Wu, Joe C

Bioorganic & medicinal chemistry letters

2010 Volume 20, Issue 16, Page(s) 4885–4891

Abstract: By targeting an extended region of the conventional 'DFG-out' pocket of p38alpha, while minimizing interactions with the specificity pocket and eliminating interactions with the adenine binding site, we are able to design and synthesize a number of ... ...

Abstract	By targeting an extended region of the conventional 'DFG-out' pocket of p38alpha, while minimizing interactions with the specificity pocket and eliminating interactions with the adenine binding site, we are able to design and synthesize a number of pyrazole-urea based DFG-out p38alpha inhibitors with good potencies, and excellent selectivity.
MeSH term(s)	Adenine/metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; Binding Sites ; Humans ; Microsomes/metabolism ; Mitogen-Activated Protein Kinase 14/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 14/metabolism ; Phenylurea Compounds/chemical synthesis ; Phenylurea Compounds/chemistry ; Phenylurea Compounds/pharmacology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Pyrazoles/chemical synthesis ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Structure-Activity Relationship
Chemical Substances	Phenylurea Compounds ; Protein Kinase Inhibitors ; Pyrazoles ; Mitogen-Activated Protein Kinase 14 (EC 2.7.11.24) ; Adenine (JAC85A2161)
Language	English
Publishing date	2010-08-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2010.06.073
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Article: Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms.

Thiel, Melissa J / Schaefer, Caralee J / Lesch, Mark E / Mobley, James L / Dudley, David T / Tecle, Haile / Barrett, Stephen D / Schrier, Denis J / Flory, Craig M

Arthritis and rheumatism

2007 Volume 56, Issue 10, Page(s) 3347–3357

Abstract: Objective: To evaluate the role of the MEK/ERK MAP kinase pathway in murine collagen-induced arthritis (CIA) using the selective MEK inhibitor PD184352. We examined the effects of the inhibitor in cytokine-stimulated synovial fibroblasts and in cytokine- ...

Abstract	Objective: To evaluate the role of the MEK/ERK MAP kinase pathway in murine collagen-induced arthritis (CIA) using the selective MEK inhibitor PD184352. We examined the effects of the inhibitor in cytokine-stimulated synovial fibroblasts and in cytokine-induced arthritis in rabbits to investigate its antiinflammatory mechanisms. Methods: Murine CIA was used to assess the effects of the selective MEK inhibitor on paw edema, clinical scores, weight loss, histopathologic features, and joint levels of p-ERK. Western blotting and immunohistochemistry techniques were used to assess p-ERK in human and rabbit synovial fibroblasts and synovial tissue from rheumatoid arthritis (RA) patients. Interleukin-1alpha (IL-1alpha)-stimulated stromelysin production in rabbit synovial fibroblasts was assessed by enzyme-linked immunosorbent assay. A rabbit IL-1alpha-induced arthritis model was used to assess the effects of the inhibitor on IL-1alpha-induced MEK activity, stromelysin production, and cartilage degradation. Results: In the CIA model, PD184352 inhibited paw edema and clinical arthritis scores in a dose-dependent manner. Disease-induced weight loss and histopathologic changes were also significantly improved by treatment. Inhibition of disease-induced p-ERK levels in the joints was seen with the inhibitor. Levels of p-ERK in the synovium were higher in RA patients than in normal individuals. PD184352 reduced IL-1alpha-induced p-ERK levels in human RA synovial fibroblasts. The production of p-ERK and stromelysin was also inhibited in IL-1alpha-stimulated rabbit synovial fibroblasts. We observed IL-1alpha-induced p-ERK in the synovial lining, subsynovial vasculature, and articular chondrocytes. IL-1alpha-induced stromelysin production and proteoglycan loss from the articular cartilage were reduced by PD184352. Conclusion: These data demonstrate the inhibition of murine CIA by PD184352, support the hypothesis that antiinflammatory activity contributes to the mechanism of action of the inhibitor, and suggest that a selective inhibitor may effectively treat RA and other inflammatory disorders.
MeSH term(s)	Animals ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/enzymology ; Benzamides/pharmacology ; Blotting, Western ; Cartilage, Articular/drug effects ; Cartilage, Articular/enzymology ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; Immunohistochemistry ; In Vitro Techniques ; MAP Kinase Kinase Kinases/drug effects ; MAP Kinase Kinase Kinases/metabolism ; Male ; Mice ; Mice, Inbred DBA ; Rabbits
Chemical Substances	2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide ; Benzamides ; Enzyme Inhibitors ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; MAP Kinase Kinase Kinases (EC 2.7.11.25)
Language	English
Publishing date	2007-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	127294-9
ISSN	1529-0131 ; 0004-3591 ; 2326-5191
ISSN (online)	1529-0131
ISSN	0004-3591 ; 2326-5191
DOI	10.1002/art.22869
Database	MEDical Literature Analysis and Retrieval System OnLINE

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