ABSTRACT
The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Drug Design , Piperazines/pharmacokinetics , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Stilbenes/pharmacokinetics , Animals , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/chemistry , Guinea Pigs , Half-Life , Microsomes, Liver/metabolism , Piperazines/chemical synthesis , Piperazines/chemistry , Stereoisomerism , Stilbenes/chemical synthesis , Stilbenes/chemistry , Structure-Activity RelationshipABSTRACT
Metabolic Syndrome, also referred to as 'Syndrome X' or 'Insulin Resistance Syndrome,' remains a major, unmet medical need despite over 30years of intense effort. Recent research suggests that there may be a causal link between this condition and abnormal glucocorticoid processing. Specifically, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis leads to increased systemic cortisol concentrations. Cushing' syndrome, a disorder that is also typified by a marked elevation in levels of cortisol, produces clinical symptomology that is similar to those observed in MetS, and they can be alleviated by decreasing circulating cortisol concentrations. As a result, it has been suggested that decreasing systemic cortisol concentration might have a positive impact on the progression of MetS. This could be accomplished through inhibition of enzymes in the cortisol synthetic pathway, 11ß-hydroxylase (Cyp11B1), 17α-hydroxylase-C17,20-lyase (Cyp17), and 21-hydroxylase (Cyp21). We have identified a series of novel sulfonamide analogs of (2S,4R)-Ketoconazole that are potent inhibitors of these enzymes. In addition, selected members of this class of compounds have pharmacokinetic properties consistent with orally delivered drugs, making them well suited to further investigation as potential therapies for MetS.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Ketoconazole/analogs & derivatives , Ketoconazole/pharmacology , Metabolic Syndrome/drug therapy , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Drug Design , Female , Guinea Pigs , Humans , Ketoconazole/pharmacokinetics , Male , Metabolic Syndrome/enzymology , Sulfonamides/pharmacokineticsABSTRACT
Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT(1A) receptor affinities. Their design, synthesis and structure-activity relationships are described.
Subject(s)
Benzofurans/chemistry , Benzofurans/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Protein Binding/physiology , Structure-Activity RelationshipABSTRACT
C5a is a terminal product of the complement cascade that activates and attracts inflammatory cells including granulocytes, mast cells and macrophages via a specific GPCR, the C5a receptor (C5aR). Inhibition of C5a/C5aR interaction has been shown to be efficacious in several animal models of autoimmune diseases, including RA, SLE and asthma. This account reports the discovery of a new class of C5aR antagonists through high-throughput screening. The lead compounds in this series are selective and block C5a binding, C5a-promoted calcium flux in human neutrophils with nanomolar potency.
Subject(s)
Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Sulfonamides/chemistry , Animals , Cell Line , High-Throughput Screening Assays , Humans , Mice , Molecular Conformation , Neutrophils/immunology , Neutrophils/metabolism , Protein Binding , Receptor, Anaphylatoxin C5a/metabolism , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
Using a focused screen of biogenic amine compounds we identified a novel series of H(3)R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models.
Subject(s)
Benzamides/chemistry , Benzimidazoles/chemistry , Histamine H3 Antagonists/chemistry , Pyrrolidines/chemistry , Receptors, Histamine H3 , Animals , Benzamides/blood , Benzamides/metabolism , Benzimidazoles/blood , Benzimidazoles/metabolism , Caco-2 Cells , Cell Line , Histamine H3 Antagonists/blood , Histamine H3 Antagonists/metabolism , Humans , Indoles/blood , Indoles/chemistry , Indoles/metabolism , Protein Binding , Pyrrolidines/blood , Pyrrolidines/metabolism , Rats , Receptors, Histamine H3/blood , Receptors, Histamine H3/metabolismABSTRACT
This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Binding Sites , Binding, Competitive , Cell Line, Tumor , Computer Simulation , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , TOR Serine-Threonine KinasesABSTRACT
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Hydantoins/chemistry , Imidazoles/chemistry , Amyloid Precursor Protein Secretases/metabolism , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Hydantoins/chemical synthesis , Hydantoins/pharmacology , Hydrogen Bonding , Imidazoles/chemical synthesis , Imidazoles/pharmacologyABSTRACT
Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Isoleucine/analogs & derivatives , Receptor, Notch1/metabolism , Alcohols , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Protein Precursor/chemistry , Animals , Drug Design , Humans , Isoleucine/chemistry , Models, Chemical , Propanolamines/chemistry , Sulfonamides/chemistryABSTRACT
A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1' moiety was identified as inhibitors of TNF-alpha converting enzyme (TACE). The structure-activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid (12p) has the best in vitro potency against isolated TACE enzyme with an IC(50) of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Sulfonamides/chemistry , Tryptophan/analogs & derivatives , ADAM17 Protein , Animals , Carboxylic Acids/chemistry , Cell Line , Enzyme Activation/drug effects , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Tryptophan/chemical synthesis , Tryptophan/chemistry , Tryptophan/pharmacologyABSTRACT
Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for activating many signaling proteins and is a promising target in tumor biology. We have identified small-molecule benzisoxazole derivatives as Hsp90 inhibitors. Crystallographic studies show that these compounds bind in the ATP binding pocket interacting with the Asp93. Structure based optimization led to the identification of potent analogues, such as 13, with good biochemical profiles.
Subject(s)
Antineoplastic Agents/chemical synthesis , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Isoxazoles/chemical synthesis , Adenosine Triphosphate/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , HSP90 Heat-Shock Proteins/metabolism , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , K562 Cells , Models, Molecular , Protein Conformation , Structure-Activity RelationshipABSTRACT
The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC(50)=3.7 microM), was recently described, representing a new small molecule lead. Initial SAR investigation demonstrated the potential of accessing the nearby S(3) and S(1)(') substrate binding pockets of the BACE-1 enzyme by building substituents off one of the phenyl substituents and guanidinyl functional group. We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Guanidine/pharmacology , Pyrroles/chemistry , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Enzyme Inhibitors/chemistry , Guanidine/chemistry , HumansABSTRACT
Using a cell-based assay, we have identified a new series of Notch-sparing gamma-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved gamma-secretase inhibitory potency and Notch-sparing selectivity.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Receptors, Notch/metabolism , Alzheimer Disease/drug therapy , Amyloid/chemistry , Amyloid Precursor Protein Secretases/chemistry , Carbon/chemistry , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Chemical , Receptors, Notch/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Combinatorial Chemistry Techniques , Guanidines/chemical synthesis , Guanidines/pharmacology , Pyrroles/chemistry , Crystallography, X-Ray , Guanidines/chemistry , Molecular Conformation , Molecular Structure , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
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/metabolismABSTRACT
Through high throughput screening, substituted proline sulfonamide 6 was identified as HCV NS5b RNA-dependent RNA polymerase inhibitor. Optimization of various regions of the lead molecule resulted in compounds that displayed good potency and selectivity. The crystal structure of 6 and NS5b polymerase complex confirmed the binding near the active site region. The optimization approach and SAR are discussed in detail.
Subject(s)
Antiviral Agents/chemical synthesis , Proline/analogs & derivatives , Proline/chemical synthesis , Sulfonamides/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Antiviral Agents/chemistry , Binding Sites , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Proline/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).
Subject(s)
Amyloid Precursor Protein Secretases/chemistry , Guanidines/chemical synthesis , Peptides/chemistry , Protease Inhibitors/chemical synthesis , Catalytic Domain , Crystallography, X-Ray , Guanidines/chemistry , Hydrogen Bonding , Models, Molecular , Molecular Mimicry , Molecular Structure , Protease Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
5-Arylsulfonylamido-3-(pyrrolidin-2-ylmethyl)-1H-indoles have been identified as high-affinity 5-HT(6) receptor ligands. Within this class, several of the (R)-enantiomers were potent agonists having EC(50) values of 1 nM or less and functioning as full agonists while the (S)-enantiomers displayed moderate antagonist activity.
Subject(s)
Indoles/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Serotonin/drug effects , Sulfonamides/chemical synthesis , Cyclic AMP/agonists , Cyclic AMP/antagonists & inhibitors , Cyclic AMP/biosynthesis , HeLa Cells , Humans , Indoles/chemistry , Indoles/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
A series of pyrazolo[4,3-d]pyrimidine sulfonamides and pyrazolo[3,4-d]pyrimidine sulfonamides have been synthesized. These compounds increase transcription of a calcitonin-luciferase promoter and production of cellular calcitonin in a calcitonin-secretion/RIA assay with minimized phosphodiesterase type 4 inhibitory activity at 30 microM as compared to structurally related xanthine methylene ketones such as denbufyllene. These two series are notable examples of small molecules that act as CT-inducers, a method to potentially treat bone loss diseases.
Subject(s)
Calcitonin/biosynthesis , Pyrimidines/chemical synthesis , Sulfonamides/chemical synthesis , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Calcitonin/genetics , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 4 , Genes, Reporter , Humans , Luciferases/genetics , Luciferases/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Radioimmunoassay , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transcriptional Activation , Xanthines/chemistry , Xanthines/pharmacologyABSTRACT
Through high throughput screening of various libraries, substituted styryl naphthalene 6 was identified as an HCMV protease inhibitor. Optimization of various regions of the lead molecule using parallel synthesis resulted in 1,6-substituted naphthalenes 19d-i. These compounds displayed good potency and were selective over elastase, trypsin, and chymotrypsin. The optimization approach on lead compound 6 in three different regions of the molecule using parallel solution-phase synthesis and the corresponding SAR are discussed in detail.
Subject(s)
2-Naphthylamine/chemical synthesis , Cytomegalovirus/chemistry , Naphthalenes/chemical synthesis , Protease Inhibitors/chemical synthesis , Serine Endopeptidases/chemistry , Sulfonamides/chemical synthesis , 2-Naphthylamine/analogs & derivatives , 2-Naphthylamine/chemistry , Databases, Factual , Naphthalenes/chemistry , Protease Inhibitors/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A novel series of HCV NS5B RNA-dependent RNA polymerase inhibitors containing a pyrano[3,4-b]indole scaffold is described leading to the discovery of compound 16, a highly potent and selective inhibitor that is active in the replicon system.