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2.
Bioorg Med Chem Lett ; 23(23): 6363-9, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24138939

ABSTRACT

Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.


Subject(s)
Amides/pharmacology , Heterocyclic Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Animals , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Male , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Rats , Rats, Sprague-Dawley , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Stereoisomerism , Structure-Activity Relationship
3.
J Med Chem ; 54(22): 7860-83, 2011 Nov 24.
Article in English | MEDLINE | ID: mdl-22039836

ABSTRACT

A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Imidazoles/chemical synthesis , Piperidines/chemical synthesis , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/etiology , Arthritis, Experimental/pathology , Cell Line, Tumor , Cell Membrane Permeability , Cell Proliferation/drug effects , Crystallography, X-Ray , Female , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , In Vitro Techniques , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Conformation , Rats , Rats, Inbred Lew , Receptor, Macrophage Colony-Stimulating Factor/chemistry , Solubility , Stereoisomerism , Structure-Activity Relationship
4.
J Med Chem ; 54(1): 233-47, 2011 Jan 13.
Article in English | MEDLINE | ID: mdl-21128593

ABSTRACT

Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that is thermoresponsive to cool to cold temperatures (8-28 °C) and also may be activated by chemical agonists such as menthol and icilin. Antagonism of TRPM8 activation is currently under investigation for the treatment of painful conditions related to cold, such as cold allodynia and cold hyperalgesia. The design, synthesis, and optimization of a class of selective TRPM8 antagonists based on a benzimidazole scaffold is described, leading to the identification of compounds that exhibited potent antagonism of TRPM8 in cell-based functional assays for human, rat, and canine TRPM8 channels. Numerous compounds in the series demonstrated excellent in vivo activity in the TRPM8-selective "wet-dog shakes" (WDS) pharmacodynamic model and in the rat chronic constriction injury (CCI)-induced model of neuropathic pain. Taken together, the present results suggest that the in vivo antagonism of TRPM8 constitutes a viable new strategy for treating a variety of disorders associated with cold hypersensitivity, including certain types of neuropathic pain.


Subject(s)
Analgesics/chemical synthesis , Benzimidazoles/chemical synthesis , Isoxazoles/chemical synthesis , TRPM Cation Channels/antagonists & inhibitors , Administration, Oral , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Biological Availability , Constriction, Pathologic/drug therapy , Constriction, Pathologic/physiopathology , Dogs , HEK293 Cells , Humans , Hyperalgesia/drug therapy , Hyperalgesia/physiopathology , In Vitro Techniques , Isoxazoles/pharmacokinetics , Isoxazoles/pharmacology , Macaca fascicularis , Microsomes, Liver/metabolism , Neuralgia/drug therapy , Neuralgia/physiopathology , Rats , Structure-Activity Relationship
6.
Mol Cancer Ther ; 8(11): 3151-61, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19887542

ABSTRACT

There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/80(+) tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.


Subject(s)
Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Imidazoles/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Bone Neoplasms/enzymology , Bone Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Growth Processes/drug effects , Cell Line, Tumor , Female , Humans , Immunohistochemistry , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/enzymology , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Nude , Osteoclasts/drug effects , Osteoclasts/pathology , Rats , Rats, Sprague-Dawley , Receptor, Macrophage Colony-Stimulating Factor/blood , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Substrate Specificity , Xenograft Model Antitumor Assays , fms-Like Tyrosine Kinase 3/metabolism
7.
Bioorg Med Chem Lett ; 18(12): 3632-7, 2008 Jun 15.
Article in English | MEDLINE | ID: mdl-18495479

ABSTRACT

An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Phenylenediamines/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Computer Simulation , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Phenylenediamines/chemical synthesis , Phenylenediamines/chemistry , Stereoisomerism , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 18(6): 2097-102, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-18289848

ABSTRACT

A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.


Subject(s)
Macrophages/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cell Proliferation/drug effects , Fluorescence Polarization , Genes, fos/genetics , Macrophage Colony-Stimulating Factor/metabolism , Mice , Mice, Inbred C57BL , Molecular Structure , Quinolones/pharmacokinetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Spleen/metabolism , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 14(12): 3043-7, 2004 Jun 21.
Article in English | MEDLINE | ID: mdl-15149641

ABSTRACT

Activation of the classical pathway of complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of complement activation in vitro.


Subject(s)
Complement Inactivator Proteins/chemical synthesis , Complement Pathway, Classical/drug effects , Pyrazoles/chemical synthesis , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Thiazoles/chemical synthesis , Thiophenes/chemical synthesis , Binding Sites/physiology , Complement C1/metabolism , Complement Inactivator Proteins/pharmacology , Complement Pathway, Classical/physiology , Humans , Myocardial Ischemia/drug therapy , Myocardial Ischemia/enzymology , Pyrazoles/pharmacology , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacology , Thiophenes/pharmacology
11.
Bioorg Med Chem Lett ; 12(3): 491-5, 2002 Feb 11.
Article in English | MEDLINE | ID: mdl-11814826

ABSTRACT

A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with but possessing improved solubility.


Subject(s)
Amidines/chemical synthesis , Amidines/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Alkylation , Indicators and Reagents , Lithium Compounds/chemistry , Protein Binding , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacology
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