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1.
J Med Chem ; 53(16): 6122-8, 2010 Aug 26.
Article in English | MEDLINE | ID: mdl-20666458

ABSTRACT

Acidic mammalian chitinase (AMCase) is a member of the glycosyl hydrolase 18 family (EC 3.2.1.14) that has been implicated in the pathophysiology of allergic airway disease such as asthma. Small molecule inhibitors of AMCase were identified using a combination of high-throughput screening, fragment screening, and virtual screening techniques and characterized by enzyme inhibition and NMR and Biacore binding experiments. X-ray structures of the inhibitors in complex with AMCase revealed that the larger more potent HTS hits, e.g. 5-(4-(2-(4-bromophenoxy)ethyl)piperazine-1-yl)-1H-1,2,4-triazol-3-amine 1, spanned from the active site pocket to a hydrophobic pocket. Smaller fragments identified by FBS occupy both these pockets independently and suggest potential strategies for linking fragments. Compound 1 is a 200 nM AMCase inhibitor which reduced AMCase enzymatic activity in the bronchoalveolar lavage fluid in allergen-challenged mice after oral dosing.


Subject(s)
Chitinases/antagonists & inhibitors , Models, Molecular , Piperazines/chemical synthesis , Triazoles/chemical synthesis , Allergens/immunology , Animals , Bronchoalveolar Lavage Fluid , Catalytic Domain , Crystallography, X-Ray , Female , Hydrophobic and Hydrophilic Interactions , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred C57BL , Piperazines/chemistry , Piperazines/pharmacology , Protein Binding , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/enzymology , Respiratory Hypersensitivity/immunology , Structure-Activity Relationship , Surface Plasmon Resonance , Triazoles/chemistry , Triazoles/pharmacology
2.
Bioorg Med Chem Lett ; 20(3): 1237-40, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-20042333

ABSTRACT

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/metabolism
3.
Bioorg Med Chem Lett ; 20(2): 653-6, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-19954970
4.
Bioorg Med Chem Lett ; 20(2): 662-4, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-20004096

ABSTRACT

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/pharmacology
5.
Bioorg Med Chem Lett ; 20(2): 632-5, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-19959359

ABSTRACT

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/pharmacology
6.
J Med Chem ; 52(22): 7081-9, 2009 Nov 26.
Article in English | MEDLINE | ID: mdl-19848404

ABSTRACT

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3Kgamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC(50) = 9 nM; PI3Kalpha IC(50) = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORC1 (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy.


Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Pyrimidines/pharmacology , Binding, Competitive , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , Molecular Weight , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinases/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/metabolism , Signal Transduction/drug effects , Substrate Specificity , TOR Serine-Threonine Kinases
7.
Bioorg Med Chem ; 17(11): 3857-65, 2009 Jun 01.
Article in English | MEDLINE | ID: mdl-19410464

ABSTRACT

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/pharmacology
8.
Bioorg Med Chem Lett ; 19(3): 926-9, 2009 Feb 01.
Article in English | MEDLINE | ID: mdl-19097890

ABSTRACT

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/chemistry
9.
J Med Chem ; 51(19): 5958-63, 2008 Oct 09.
Article in English | MEDLINE | ID: mdl-18783200

ABSTRACT

The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCtheta) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCtheta enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCtheta high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5-(3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low microM ATP competitive PKCtheta inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3-pyridinecarbonitrile 4p, a 70 nM PKCtheta inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCbeta, and PKCzeta, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.


Subject(s)
Indoles/pharmacology , Isoenzymes/antagonists & inhibitors , Nitriles/pharmacology , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Indoles/chemical synthesis , Indoles/chemistry , Interleukin-2/antagonists & inhibitors , Interleukin-2/biosynthesis , Isoenzymes/deficiency , Isoenzymes/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , Molecular Structure , Nitriles/chemical synthesis , Nitriles/chemistry , Protein Kinase C/deficiency , Protein Kinase C/drug effects , Protein Kinase C-theta , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Stereoisomerism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
10.
Bioorg Med Chem Lett ; 18(2): 767-71, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-18068983

ABSTRACT

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 , Humans
11.
Bioorg Med Chem Lett ; 18(3): 1063-6, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-18162398

ABSTRACT

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 Relationship
12.
J Med Chem ; 50(23): 5535-8, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17948978

ABSTRACT

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/metabolism
13.
J Med Chem ; 49(21): 6158-61, 2006 Oct 19.
Article in English | MEDLINE | ID: mdl-17034121

ABSTRACT

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 Relationship
14.
J Med Chem ; 49(11): 3052-5, 2006 Jun 01.
Article in English | MEDLINE | ID: mdl-16722622

ABSTRACT

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/chemistry
15.
Bioorg Med Chem Lett ; 16(11): 2978-81, 2006 Jun 01.
Article in English | MEDLINE | ID: mdl-16545564

ABSTRACT

1,2,4-Oxadiazolidin-3,5-dione and 1,3,5-triazin-2,4,6-trione scaffolds were employed as templates to incorporate the pharmacophore requirements of cytosolic phospholipase A2alpha substrate mimetics. Inhibitors that are active in both enzyme, and cell-based assays were identified from both classes. From the SAR work carried out and modeling efforts around these templates, the triazinetrione scaffold with an additional substitution point was found to be more favorable.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Phospholipases A/antagonists & inhibitors , Phospholipases A/metabolism , Triazines/chemistry , Triazines/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Group IV Phospholipases A2 , Models, Molecular , Molecular Structure , Oxadiazoles/chemical synthesis , Phospholipases A/chemistry , Protein Structure, Tertiary , Structure-Activity Relationship , Substrate Specificity , Triazines/chemical synthesis
16.
Bioorg Med Chem Lett ; 16(9): 2532-4, 2006 May 01.
Article in English | MEDLINE | ID: mdl-16480869

ABSTRACT

A novel class of HCV NS5B RNA dependent RNA polymerase inhibitors containing 2,3,4,9-tetrahydro-1H-carbazole and 1,2,3,4-tetrahydro-cyclopenta[b]indole scaffolds were designed and synthesized. Optimization of the aromatic region showed preference for 5,8-disubstitution pattern in both the scaffolds examined while favoring the n-propyl moiety for the C-1 position. 1,2,3,4-tetrahydro-cyclopenta[b]indole scaffold was slightly more potent than the corresponding 2,3,4,9-tetrahydro-1H-carbazole and analogue 36 displayed an IC50 of 550 nM against HCV NS5B enzyme.


Subject(s)
Antiviral Agents/chemical synthesis , Carbazoles , Cyclopentanes , Indoles , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/chemical synthesis , Viral Nonstructural Proteins/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Carbazoles/chemical synthesis , Carbazoles/chemistry , Carbazoles/pharmacology , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Drug Design , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship
17.
Bioorg Med Chem Lett ; 16(2): 457-60, 2006 Jan 15.
Article in English | MEDLINE | ID: mdl-16274990

ABSTRACT

A novel class of HCV NS5B RNA dependent RNA polymerase inhibitors containing 3,4-dihydro-1H-[1]-benzothieno[2,3-c]pyran and 3,4-dihydro-1H-pyrano[3,4-b]benzofuran scaffolds were designed and synthesized. Optimization of the alkyl substituent in the pyran ring showed preference for an n-propyl group, while 5,8-disubstitution pattern is preferred for the aromatic region. Analog 19 displayed potent activity with an IC(50) of 50 nM against HCV NS5B enzyme and was selective over a panel of polymerases.


Subject(s)
Benzofurans , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrans , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Benzofurans/chemical synthesis , Benzofurans/chemistry , Benzofurans/pharmacology , Cell Line, Tumor , Chlorocebus aethiops , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacology , RNA-Dependent RNA Polymerase/chemistry , Structure-Activity Relationship , Vero Cells , Viral Nonstructural Proteins/chemistry
18.
Bioorg Med Chem Lett ; 15(21): 4780-5, 2005 Nov 01.
Article in English | MEDLINE | ID: mdl-16125933

ABSTRACT

Several series of conformationally constrained N1-arylsulfonyltryptamine derivatives were prepared and tested for 5-HT6 receptor binding affinity and ability to modulate cAMP production in a cyclase assay. The 3-piperidin-3-yl-, 3-(1-methylpyrrolidin-2-ylmethyl)-, and 3-pyrrolidin-3-yl-1H-indole arrays (8-13) appear to be able to adopt a conformation that allows high affinity 5-HT6 receptor binding, while the beta-carboline array 14 binds with a significantly weaker (10- to 100-fold) affinity. N1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a high affinity full agonist with EC50 = 24 nM. Several of the N1-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC50 = 0.8, 1.0 nM).


Subject(s)
Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Receptor Agonists/chemical synthesis , Tryptamines/chemical synthesis , Adenylyl Cyclases/metabolism , Cyclic AMP/biosynthesis , Humans , Molecular Conformation , Protein Binding , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , Tryptamines/chemistry , Tryptamines/pharmacology
19.
Bioorg Med Chem Lett ; 15(6): 1591-4, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15745803

ABSTRACT

A novel series of p21 chemoselective agents containing a pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides were identified by high throughput screening. Optimization of the amide region by parallel synthesis and the iterative design toward understanding structure-activity relationship to improve potency are described. The isopropyl carbamate derivative 34 was identified as a highly chemoselective agent displaying a potency of 51 nM in the p21 deficient cell line.


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Cycle Proteins/physiology , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p21 , HCT116 Cells , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship
20.
J Med Chem ; 48(2): 353-6, 2005 Jan 27.
Article in English | MEDLINE | ID: mdl-15658848

ABSTRACT

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/pharmacology
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