ABSTRACT
A novel series of quinolinone-based adenosine A(2B) receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A(2B) antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM).
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Quinolones/chemistry , Receptor, Adenosine A2B/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/pharmacology , Combinatorial Chemistry Techniques , Drug Evaluation, Preclinical , Humans , Microsomes, Liver/metabolism , Quinolones/chemical synthesis , Quinolones/pharmacology , Receptor, Adenosine A2B/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of adenosine A(2A) receptor antagonists was identified by high-throughput screening of an encoded combinatorial compound collection. The initial hits were optimized for A(2A) binding affinity, A(1) selectivity, and in vitro microsomal stability generating orally available 2-aminoimidazo[4,5-b]pyridine-based A(2A) antagonist leads.
Subject(s)
Pyrimidines/pharmacology , Receptor, Adenosine A2A/drug effects , Drug Discovery , Humans , Hydrogen Bonding , Microsomes/drug effects , Receptor, Adenosine A2A/chemistryABSTRACT
A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.
Subject(s)
Adenosine A2 Receptor Antagonists , Purinones/chemical synthesis , Animals , Humans , Protein Binding/drug effects , Protein Binding/physiology , Purinones/metabolism , Purinones/pharmacology , Rats , Receptor, Adenosine A2A/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
The discovery and synthesis of a series of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A(2A) receptor antagonists from a small-molecule combinatorial library using a high-throughput radioligand-binding assay is described. Antagonists were further characterized in the A(2A) binding assay and an A(1) selectivity assay. Selected examples exhibited excellent affinity for A(2A) and good selectivity versus the A(1) receptor.
Subject(s)
Purinergic P1 Receptor Antagonists , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Alkylation , Cell Line , Combinatorial Chemistry Techniques , Drug Discovery , Humans , Radioligand Assay , Receptors, Purinergic P1/metabolism , Thiazoles/metabolismABSTRACT
At the time of writing, there are seven marketed kinase inhibitor drugs. The first kinase inhibitor, imatinib mesilate (Gleevec, Novartis), came to market in 2001, an inhibitor of the breakpoint cluster region (BCR)/Abelson murine leukemia oncogene homolog (ABL) fusion, platelet-derived growth factor (PDGF) receptor, and c-kit kinases. The most recent kinase inhibitor to come to market, disatinib (Sprycel, Bristol-Myers Squibb), acts on c-SRC, ABL and Bruton's tyrosine kinase. To date, kinase inhibitor drugs are approved for oncology and demonstrate that it is possible to develop compounds with relative selectivity for the target kinase against the broader kinome. However, the use of kinase inhibitors in chronic inflammatory and immunologic diseases may require greater selectivity for the target kinase. This review addresses the opportunities and challenges of kinase inhibition as a therapeutic approach in chronic immune and inflammatory disease.
Subject(s)
Immune System Diseases/drug therapy , Inflammation/drug therapy , Protein Kinase Inhibitors/pharmacology , Animals , Benzamides , Chronic Disease , Clinical Trials as Topic , Dasatinib , Humans , Imatinib Mesylate , Immune System Diseases/physiopathology , Inflammation/physiopathology , Piperazines/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Thiazoles/pharmacologyABSTRACT
A series of 3,4- and 3,5-disubstituted phenyl-containing cyclobutenedione analogues were synthesized and evaluated as CXCR2 receptor antagonists. Variations in the disubstitution pattern of the phenyl ring afforded new compounds with potent CXCR2 binding affinity in the low nanomolar ranges. Moreover, two potent compounds 19 and 26 exhibited good oral pharmacokinetic profiles.
Subject(s)
Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacology , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cyclobutanes/chemistry , Haplorhini , Molecular Structure , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
Gamma-secretase is a key enzyme involved in the production of beta-amyloid peptides which are believed to play a critical role in the onset and progression of Alzheimer's disease (AD). As such, inhibition of gamma-secretase has been an attractive approach to AD therapy. In this paper, the design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors are described.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Carbamates/chemistry , Carbamates/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Alzheimer Disease/enzymology , Carbamates/chemical synthesis , Drug Design , Enzyme Inhibitors/chemical synthesis , Humans , Pyrrolidines/chemistry , Quinolines/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
The discovery and evaluation of 5-(4-phenylbenzyl)oxazole-4-carboxamides as prostacyclin (IP) receptor antagonists is described. Analogs disclosed showed high affinity for the IP receptor in human platelet membranes with IC50 values of 0.05-0.50 microM, demonstrated functional antagonism by inhibiting cAMP production in HEL cells with IC50 values of 0.016-0.070 microM, and exhibited significant selectivity versus other prostanoid receptors.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Receptors, Prostaglandin/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Polycyclic Aromatic Hydrocarbons/chemical synthesis , Polycyclic Aromatic Hydrocarbons/pharmacology , Receptors, Epoprostenol , Structure-Activity RelationshipABSTRACT
Melanin concentrating hormone (MCH) plays an important role in the regulation of food intake and energy balance in mammals. MCH-1 receptor (MCH1R) deficient mice are lean and resistant to diet-induced obesity. As such, MCH1R antagonists are believed to have potential as possible treatments for obesity. The discovery of a novel class of tetralin ureas as potent MCH1R antagonists is described herein.
Subject(s)
Receptors, Somatostatin/antagonists & inhibitors , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/pharmacology , Urea/analogs & derivatives , Urea/pharmacology , Animals , Binding, Competitive/drug effects , CHO Cells , Cricetinae , Cricetulus , Drug Design , Humans , Mice , Mice, Knockout , Rats , Receptors, Somatostatin/genetics , Structure-Activity Relationship , Tetrahydronaphthalenes/pharmacokinetics , Tissue Distribution , Urea/pharmacokineticsABSTRACT
The melanin-concentrating hormone (MCH) is a hypothalamic peptide that binds to one of two receptors: MCH1 and MCH2. MCH1 is well-recognized for its orexigenic properties but may control a number of other physiological activities from both the CNS and the periphery. MCH2 is not expressed in rodents and so its physiological functions in humans are not well understood. This review highlights the discovery and development of multiple structural classes of MCH1 small-molecule antagonists that show impressive levels of efficacy in rodent models of obesity. In some cases these compounds show improved and more sustained efficacy compared to clinically-approved antiobesity pharmaceutical agents. Despite such compelling efficacy, a number of chemical series are unable to progress to the clinic due to selectivity issues. Ongoing efforts to circumvent these challenges are addressed.
ABSTRACT
Structure-activity studies on lead cyclobutenedione 3 led to the discovery of 4 (SCH 527123), a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist with excellent cell-based activity. Compound 4 displayed good oral bioavailability in rat and may be a potential therapeutic agent for the treatment of various inflammatory diseases.
Subject(s)
Benzamides/pharmacology , Cyclobutanes/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemical synthesis , Biological Availability , Cyclobutanes/administration & dosage , Cyclobutanes/chemical synthesis , Molecular Structure , Rats , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/metabolism , Structure-Activity RelationshipABSTRACT
Since its discovery as the first receptor for the orexigenic neuropeptide melanin-concentrating hormone (MCH), the MCH receptor, MCHR1, has been actively pursued for therapeutic intervention in the treatment of obesity. Mice with targeted deletion of MCHR1 or its cognate ligand, MCH, generally have decreased body weight and fat mass and are resistant to diet-induced obesity compared with their wild-type counterparts. Mice treated via intracerebroventricular infusion with MCH, or that overexpress MCH or MCHR1, exhibit weight gain compared with control animals. MCHR1 is also a central target of leptin signaling and appears to be a mediator of insulin resistance. The distribution of MCH and MCHR1 in rat brain, outside of regions that control appetite and satiety, has led to the finding that MCH signaling participates in other functions such as emotion and stress. This review will describe in detail the biological studies that show how MCH and MCHR1 control numerous physiological functions. The current status of the development of MCHR1 antagonists for clinical use will also be assessed. Given the substantial link between obesity and its many associated afflictions, a single pharmaceutical agent that could be used to treat multiple pathologies would be welcome.
ABSTRACT
Since its discovery as the first receptor for the orexigenic neuropeptide melanin-concentrating hormone (MCH), the MCH receptor, MCHR1, has been actively pursued for therapeutic intervention in the treatment of obesity. Mice with targeted deletion of MCHR1 or its cognate ligand, MCH, generally have decreased body weight and fat mass and are resistant to diet-induced obesity compared with their wild-type counterparts. Mice treated via intracerebroventricular infusion with MCH, or that overexpress MCH or MCHR1, exhibit weight gain compared with control animals. MCHR1 is also a central target of leptin signaling and appears to be a mediator of insulin resistance. The distribution of MCH and MCHR1 in rat brain, outside of regions that control appetite and satiety, has led to the finding that MCH signaling participates in other functions such as emotion and stress. This review will describe in detail the biological studies that show how MCH and MCHR1 control numerous physiological functions. The current status of the development of MCHR1 antagonists for clinical use will also be assessed. Given the substantial link between obesity and its many associated afflictions, a single pharmaceutical agent that could be used to treat multiple pathologies would be welcome.
Subject(s)
Hypothalamic Hormones/physiology , Hypothalamus/physiology , Melanins/physiology , Pituitary Hormones/physiology , Receptors, Somatostatin/physiology , Amino Acid Sequence , Animals , Body Weight/drug effects , Body Weight/physiology , Humans , Hypothalamic Hormones/antagonists & inhibitors , Hypothalamic Hormones/genetics , Hypothalamus/drug effects , Melanins/antagonists & inhibitors , Melanins/genetics , Molecular Sequence Data , Obesity/physiopathology , Obesity/prevention & control , Pituitary Hormones/antagonists & inhibitors , Pituitary Hormones/genetics , Receptors, Somatostatin/antagonists & inhibitors , Receptors, Somatostatin/genetics , Sequence Homology, Amino AcidABSTRACT
The development of structure-activity relationships (SARs) relating to the function of a biological protein is often a long and protracted undertaking when using an iterative medicinal chemistry approach. High throughput screening of ECLiPS (Encoded Combinatorial Libraries on Polymeric Support) libraries can be used to simplify this process. In this paper, we illustrate how a large ECLiPS library of 26,908 compounds, based on a tricyclic core structure, was used to define a multitude of SARs for the oncogenic target, farnesyltransferase (FTase). This library, FT-2, was prepared using a split-and-pool approach in which small molecules are constructed on resin that contains tag/linker constructs to track the synthetic process [1-5] Highly defined SARs were produced from this screen that enhanced our understanding of FTase binding site interactions. The pivotal compounds culled from this library were potent in both cell-free and cell-based FTase assays, selective over the closely related enzyme, geranylgeranyltransferase I (GGTase I), and inhibited the adherent-independent growth of a transformed cell line.
Subject(s)
Combinatorial Chemistry Techniques , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Alkyl and Aryl Transferases/antagonists & inhibitors , Binding Sites , Biological Assay , Cell Culture Techniques , Cell Line, Transformed/drug effects , Molecular Structure , Structure-Activity Relationship , Tumor Cells, Cultured/drug effectsABSTRACT
A novel series of 3,4-diaminocyclobut-3-ene-1,2-diones was prepared and found to show potent inhibitory activity of CXCR2 binding and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Microsome stability and Caco2 studies were subsequently used to show that compounds of this chemotype are predicted to have good oral bioavailability and are thus suitable for pharmaceutical development.
Subject(s)
Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacology , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Biological Availability , Caco-2 Cells , Cyclobutanes/chemistry , Cyclobutanes/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Structure-Activity RelationshipABSTRACT
Farnesyltransferase inhibitors identified from an ECLiPS library were optimized using solution-phase synthesis. X-ray crystallography of inhibited complexes was used to identify substructures that coordinate to the active site zinc. The X-ray structures were ultimately used to guide the design of second-generation analogs with FTase IC(50)s of less than 1.0 nM.
Subject(s)
Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Peptide Library , Zinc/chemistry , Animals , Binding Sites , Catalysis , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Farnesyltranstransferase/chemical synthesis , Inhibitory Concentration 50 , Mice , NIH 3T3 Cells , Structure-Activity RelationshipABSTRACT
In order to fully explore structure-activity relationships at the 1- and 2-positions of the piperazine core of tricyclic farnesyltransferase inhibitors, an 11,718-member ECLiPS library was synthesized and screened in a farnesyltransferase scintillation proximity assay. A detailed description of the library and analyses of the screening data will be provided.
Subject(s)
Enzyme Inhibitors/chemistry , Farnesyltranstransferase/antagonists & inhibitors , Piperazines/chemistry , Piperazines/pharmacology , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Kinetics , Structure-Activity RelationshipABSTRACT
-4-Amino-2-arylbutylbenzamides such as 1 were identified as micromolar MCH 1 receptor (MCH1R) antagonists via screening using a scintillation proximity assay based on [125I]-MCH binding to recombinant, human MCH1R. Subsequent lead optimization efforts using solid-phase parallel synthesis resulted in the defined structure-activity relationships and the identification of 4-amino-2-biarylbutylureas, such as 11g, as potent single digit nanomolar MCH1R antagonists.
Subject(s)
Receptors, Somatostatin/antagonists & inhibitors , Urea/chemical synthesis , Urea/pharmacology , Combinatorial Chemistry Techniques , Drug Evaluation, Preclinical , Humans , Molecular Structure , Structure-Activity Relationship , Urea/analogs & derivativesABSTRACT
An encoded combinatorial library based on aryl and biaryl piperidine scaffolds was designed and synthesized. Screening of this library resulted in the discovery of high-nanomolar biaryl piperidine-based MCH1 receptor antagonists. Follow-up optimization using a parallel synthesis provided potent, single digit nanomolar antagonists.
