ABSTRACT
This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.
Subject(s)
Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Animals , Arthritis/chemically induced , Arthritis/prevention & control , Collagen , Dogs , Drug Design , Drug Discovery , Histamine , Indicators and Reagents , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Molecular , Pruritus/chemically induced , Pruritus/prevention & control , Rats , Rats, Sprague-Dawley , Receptors, Histamine , Receptors, Histamine H4 , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Computer aided modeling guided the design of a series of diarylimidazole compounds (11-22) intended to interact with both the ATP and adjacent allosteric binding domains of B-RAF kinase. Their ability to inhibit the function of B-RAF kinase and intracellular ERK1/2 phosphorylation were evaluated.
Subject(s)
Computer-Aided Design , Hydrocarbons, Aromatic/pharmacology , Imidazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Allosteric Site , Crystallography, X-Ray , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Hydrocarbons, Aromatic/chemical synthesis , Imidazoles/chemical synthesis , Inhibitory Concentration 50 , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
B-RAF mutations have been identified in the majority of melanoma and a large fraction of colorectal and papillary thyroid carcinoma. Drug discovery efforts targeting mutated B-RAF have yielded several interesting molecules, and currently, three compounds are undergoing clinical evaluation. Inhibition of B-RAF in animal models leads to a slowing of tumor growth and, in some cases, tumor reduction. Described within is a novel series of diaryl imidazoles with potent, single-digit nanomolar, anti-B-RAF activity. One compound from this series has been detailed here and has been shown to block B-RAF(V600E)-dependent extracellular signal-regulated kinase 1/2 phosphorylation in SK-MEL-28 melanoma cells as well as soft agar colony formation and proliferation. Importantly, interleukin-8 (IL-8) was identified by quantitative real-time PCR and ELISA as a product of the elevated mitogen-activated protein kinase signaling in these cells. Plasma concentrations of IL-8 in mice bearing melanoma xenografts were significantly reduced following exposure to B-RAF inhibitors. Taken together, these data suggest that IL-8 could serve as a tractable clinical biomarker.
Subject(s)
Biomarkers, Tumor/metabolism , Interleukin-8/antagonists & inhibitors , Melanoma/metabolism , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme-Linked Immunosorbent Assay , Humans , Imidazoles/pharmacology , Interleukin-8/biosynthesis , Interleukin-8/genetics , Melanoma/pathology , Phosphorylation , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/genetics , Transplantation, HeterologousABSTRACT
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.
Subject(s)
Chemistry, Pharmaceutical/methods , Receptor, Cannabinoid, CB2/chemistry , Sulfones/chemistry , Animals , Drug Design , Drug Evaluation, Preclinical , Kinetics , Ligands , Models, Chemical , Protein Binding , Rats , Receptors, Drug , Sodium/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationships of a series of novel phenoxyphenyl diamine derivatives with affinity for both the histamine H(3) receptor and the serotonin transporter is described.
Subject(s)
Diamines/chemistry , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Receptors, Histamine H3/drug effects , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Histamine Antagonists/chemical synthesis , Humans , Molecular Structure , Receptors, Histamine H3/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of novel and potent pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. A highly regio- and diastereoselective synthesis of the pyrrolidino-tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH(3) was developed. In vitro and in vivo data are discussed.
Subject(s)
Chemistry, Pharmaceutical/methods , Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacology , Receptors, Histamine H3/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/chemistry , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/pharmacology , Animals , Depression/drug therapy , Drug Design , Humans , Kinetics , Models, Chemical , Molecular Conformation , RatsABSTRACT
A variety of alpha-amino acid derivatives were prepared as glycine transport inhibitors and their ability to block the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter-2 (hGlyT-2) was evaluated. An array of substituents at the chiral center was studied and overall, L-phenylalanine was identified as the preferred amino acid residue. Compounds prepared from l-amino acids were more potent GlyT-2 inhibitors than analogs derived from the corresponding d-amino acids. Introducing an achiral amino acid such as glycine, or incorporating geminal substitution in the alpha-position, led to a significant reduction in GlyT-2 inhibitory properties.
Subject(s)
Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Amino Acids/chemistry , Amino Acids/pharmacology , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Amino Acid Transport Systems, Neutral/genetics , Amino Acids/chemical synthesis , Animals , Biological Transport/drug effects , COS Cells , Chlorocebus aethiops , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins , Neurotransmitter Uptake Inhibitors/chemical synthesis , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacologyABSTRACT
Several beta- and gamma-amino acid derivatives were prepared as glycine transport inhibitors and their ability to block the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter-2 (hGlyT-2) were evaluated. A range of lipophilic side chains were tolerated in the beta-amino acid series (i.e., Ph, CH(2)Ph, CH(CH(3))(2), and CH(2)CH(CH(3))(2)). In the gamma-amino acid series, minimal differences in potency were observed between the alpha,beta-unsaturated analogs and the corresponding saturated derivatives. In both series, a 4-biphenyl or 4-phenoxyphenyl substituent appended to the urea or cyanogunaidine moiety was necessary for in vitro activity.
Subject(s)
Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Amino Acids/chemistry , Amino Acids/pharmacology , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Amino Acid Transport Systems, Neutral/genetics , Amino Acids/chemical synthesis , Animals , Biological Transport/drug effects , COS Cells , Chlorocebus aethiops , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins , Guanidines/chemistry , Neurotransmitter Uptake Inhibitors/chemical synthesisABSTRACT
A series of benzoylpiperidine analogs related to 4a was prepared, and their ability to inhibit the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter type-2 (GlyT-2) was evaluated. Small structural changes to the benzoylpiperidine region of the molecule led to a significant decrease in GlyT-2 inhibitory activity. In contrast, the distal aryl ring was more tolerant to functional group modifications and could accommodate a variety of substitutes at the C-2 or C-3 positions. Comparable activities to 4a were obtained by replacing the anilino nitrogen with an ether linkage 27 or by exchanging the isopropoxy ether moiety with an isopropyl amino group 15. A distinct preference for a 2-carbon tether (n=1) was observed relative to the corresponding 3-carbon homolog (n=2).
