Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 38
Filter
Add more filters










Publication year range
1.
ACS Med Chem Lett ; 10(11): 1554-1560, 2019 Nov 14.
Article in English | MEDLINE | ID: mdl-31749910

ABSTRACT

A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

2.
Clin Cancer Res ; 25(1): 300-311, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30206163

ABSTRACT

PURPOSE: Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials. EXPERIMENTAL DESIGN: We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations. RESULTS: In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK-STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone. CONCLUSIONS: Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.


Subject(s)
Cell Cycle Proteins/genetics , Multiple Myeloma/drug therapy , Organic Chemicals/pharmacology , Receptors, Interleukin-6/genetics , STAT3 Transcription Factor/genetics , Transcription Factors/genetics , Animals , Cell Cycle Proteins/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Heterografts , Histone-Lysine N-Methyltransferase/genetics , Humans , Janus Kinases/genetics , Mice , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Protein Binding/drug effects , Proteins/antagonists & inhibitors , Proteins/genetics , Proto-Oncogene Proteins c-myc/genetics , Receptor, Fibroblast Growth Factor, Type 3/genetics , Repressor Proteins/genetics , Signal Transduction/drug effects , Transcription Factors/antagonists & inhibitors
3.
ACS Med Chem Lett ; 8(5): 486-491, 2017 May 11.
Article in English | MEDLINE | ID: mdl-28523098

ABSTRACT

A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.

4.
Drug Metab Dispos ; 44(10): 1668-74, 2016 10.
Article in English | MEDLINE | ID: mdl-27457784

ABSTRACT

Epacadostat (EPA, INCB024360) is a first-in-class, orally active, investigational drug targeting the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In Phase I studies, EPA has demonstrated promising clinical activity when used in combination with checkpoint modulators. When the metabolism of EPA was investigated in humans, three major, IDO1-inactive, circulating plasma metabolites were detected and characterized: M9, a direct O-glucuronide of EPA; M11, an amidine; and M12, N-dealkylated M11. Glucuronidation of EPA to form M9 is the dominant metabolic pathway, and in vitro, this metabolite is formed by UGT1A9. However, negligible quantities of M11 and M12 were detected when EPA was incubated with a panel of human microsomes from multiple tissues, hepatocytes, recombinant human cytochrome P450s (P450s), and non-P450 enzymatic systems. Given the reductive nature of M11 formation and the inability to define its source, the role of gut microbiota was investigated. Analysis of plasma from mice dosed with EPA following pretreatment with either antibiotic (ciprofloxacin) to inhibit gut bacteria or 1-aminobenzotriazole (ABT) to systemically inhibit P450s demonstrated that gut microbiota is responsible for the formation of M11. Incubations of EPA in human feces confirmed the role of gut bacteria in the formation of M11. Further, incubations of M11 with recombinant P450s showed that M12 is formed via N-dealkylation of M11 by CYP3A4, CYP2C19, and CYP1A2. Thus, in humans three major plasma metabolites of EPA were characterized: two primary metabolites, M9 and M11, formed directly from EPA via UGT1A9 and gut microbiota, respectively, and M12 formed as a secondary metabolite via P450s from M11.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Glucuronosyltransferase/metabolism , Intestines/microbiology , Microbiota , Oximes/metabolism , Sulfonamides/metabolism , Humans , Proton Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , UDP-Glucuronosyltransferase 1A9
6.
Bioorg Med Chem Lett ; 21(22): 6909-15, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21974952
7.
Blood ; 115(17): 3520-30, 2010 Apr 29.
Article in English | MEDLINE | ID: mdl-20197554

ABSTRACT

Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC(50) values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86(high) DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.


Subject(s)
Dendritic Cells/immunology , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Neoplasms/immunology , T-Lymphocytes/immunology , Animals , Apoptosis/drug effects , Apoptosis/immunology , B7-2 Antigen/immunology , B7-2 Antigen/metabolism , Coculture Techniques , Dendritic Cells/enzymology , Dose-Response Relationship, Drug , HeLa Cells , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasms/drug therapy , Neoplasms/enzymology , T-Lymphocytes/enzymology , Tryptophan Oxygenase/immunology , Tryptophan Oxygenase/metabolism
8.
Mol Cancer Ther ; 9(2): 489-98, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20124451

ABSTRACT

Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose- and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients.


Subject(s)
Amidines/pharmacology , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Neoplasms/metabolism , Tryptophan/metabolism , Animals , Cell Line, Tumor , Dogs , Female , Humans , Immune System , Immunotherapy/methods , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Kynurenine/pharmacology , Lymph Nodes/pathology , Lymphocytes/immunology , Mice , Mice, Inbred BALB C , Neoplasms/drug therapy , Neoplasms/pathology
9.
Blood ; 115(14): 2919-27, 2010 Apr 08.
Article in English | MEDLINE | ID: mdl-20154217

ABSTRACT

The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.


Subject(s)
Hematologic Neoplasms/drug therapy , Janus Kinase 2/antagonists & inhibitors , Mutation, Missense , Primary Myelofibrosis/drug therapy , Protein Kinase Inhibitors/pharmacology , Receptors, Thrombopoietin/metabolism , Thrombocytosis/drug therapy , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Drug Screening Assays, Antitumor/methods , Female , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Humans , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Mice , Mice, Inbred BALB C , Phosphorylation/drug effects , Phosphorylation/genetics , Platelet Count , Primary Myelofibrosis/blood , Primary Myelofibrosis/genetics , Receptors, Thrombopoietin/genetics , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , STAT5 Transcription Factor/genetics , STAT5 Transcription Factor/metabolism , Signal Transduction/drug effects , Thrombocytosis/blood , Thrombocytosis/genetics
10.
Neoplasia ; 12(1): 28-38, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20072651

ABSTRACT

Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways in tumor cells and promote tumor growth, survival, and drug resistance. INCB16562 was developed as a novel, selective, and orally bioavailable small-molecule inhibitor of JAK1 and JAK2 markedly selective over JAK3. The specific cellular activity of the inhibitor was demonstrated by its potent and dose-dependent inhibition of cytokine-dependent JAK/STAT signaling and cell proliferation in the absence of effects on Bcr-Abl-expressing cells. Treatment of myeloma cells with INCB16562 potently inhibited interleukin-6 (IL-6)-induced phosphorylation of STAT3. Moreover, the proliferation and survival of myeloma cells dependent on IL-6 for growth, as well as the IL-6-induced growth of primary bone marrow-derived plasma cells from a multiple myeloma patient, were inhibited by INCB16562. Induction of caspase activation and apoptosis was observed and attributed, at least in part, to the suppression of Mcl-1 expression. Importantly, INCB16562 abrogated the protective effects of recombinant cytokines or bone marrow stromal cells and sensitized myeloma cells to cell death by exposure to dexamethasone, melphalan, or bortezomib. Oral administration of INCB16562 antagonized the growth of myeloma xenografts in mice and enhanced the antitumor activity of relevant agents in combination studies. Taken together, these data suggest that INCB16562 is a potent JAK1/2 inhibitor and that mitigation of JAK/STAT signaling by targeting JAK1 and JAK2 will be beneficial in the treatment of myeloma patients, particularly in combination with other agents.


Subject(s)
Azepines/pharmacology , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Multiple Myeloma/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Stromal Cells/drug effects , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Azepines/administration & dosage , Azepines/chemistry , Blotting, Western , Boronic Acids/administration & dosage , Bortezomib , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cells, Cultured , Coculture Techniques , Humans , Interleukin-6/pharmacology , Janus Kinase 1/metabolism , Janus Kinase 2/metabolism , Melphalan/administration & dosage , Mice , Mice, SCID , Molecular Structure , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Phosphorylation/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrazines/administration & dosage , Pyridines/administration & dosage , Pyridines/chemistry , STAT3 Transcription Factor/metabolism , Stromal Cells/cytology , Treatment Outcome , Xenograft Model Antitumor Assays
12.
Clin Cancer Res ; 15(22): 6891-900, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19887489

ABSTRACT

PURPOSE: Deregulation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is a hallmark for the Philadelphia chromosome-negative myeloproliferative diseases polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We tested the efficacy of a selective JAK1/2 inhibitor in cellular and in vivo models of JAK2-driven malignancy. EXPERIMENTAL DESIGN: A novel inhibitor of JAK1/2 was characterized using kinase assays. Cellular effects of this compound were measured in cell lines bearing the JAK2V617F or JAK1V658F mutation, and its antiproliferative activity against primary polycythemiavera patient cells was determined using clonogenic assays. Antineoplastic activity in vivo was determined using a JAK2V617F-driven xenograft model, and effects of the compound on survival, organomegaly, body weight, and disease-associated inflammatory markers were measured. RESULTS: INCB16562 potently inhibited proliferation of cell lines and primary cells from PV patients carrying the JAK2V617F or JAK1V658F mutation by blocking JAK-STAT signaling and inducing apoptosis. In vivo, INCB16562 reduced malignant cell burden, reversed splenomegaly and normalized splenic architecture, improved body weight gains, and extended survival in a model of JAK2V617F-driven hematologic malignancy. Moreover, these mice suffered from markedly elevated levels of inflammatory cytokines, similar to advanced myeloproliferative disease patients, which was reversed upon treatment. CONCLUSIONS: These data showed that administration of the dual JAK1/2 inhibitor INCB16562 reduces malignant cell burden, normalizes spleen size and architecture, suppresses inflammatory cytokines, improves weight gain, and extends survival in a rodent model of JAK2V617F-driven hematologic malignancy. Thus, selective inhibitors of JAK1 and JAK2 represent a novel therapy for the patients with myeloproliferative diseases and other neoplasms associated with JAK dysregulation.


Subject(s)
Enzyme Inhibitors/pharmacology , Janus Kinase 1/genetics , Janus Kinase 1/metabolism , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Mutation , Animals , Antineoplastic Agents/pharmacology , Apoptosis , Cell Line, Tumor , Cell Proliferation , Humans , Inhibitory Concentration 50 , Kinetics , Mice , Neoplasm Transplantation , Polycythemia Vera/drug therapy
13.
J Med Chem ; 52(23): 7364-7, 2009 Dec 10.
Article in English | MEDLINE | ID: mdl-19507862

ABSTRACT

A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (IDO). Optimization led to the identification of 5l, which is a potent (HeLa IC(50) = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy in mice bearing GM-CSF-secreting B16 melanoma tumors.


Subject(s)
Binding, Competitive , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Melanoma/enzymology , Amidines/chemistry , Amidines/metabolism , Amidines/pharmacology , Amidines/therapeutic use , Animals , Disease Models, Animal , Disease Progression , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Gene Expression Regulation, Neoplastic/drug effects , HeLa Cells , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry , Inhibitory Concentration 50 , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Mice , Models, Molecular , Molecular Conformation
14.
J Med Chem ; 52(14): 4161-72, 2009 Jul 23.
Article in English | MEDLINE | ID: mdl-19552436

ABSTRACT

A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. Selected compounds proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, we describe an in vitro intrinsic clearance-based approach to the optimization of pyrazinone-based CRF(1) receptor antagonists wherein sites of metabolism were identified by incubation with human liver microsomes. It was found that the rate of metabolism could be decreased by incorporation of appropriate substituents at the primary sites of metabolism. This led to the discovery of compound 12x, a highly potent (IC(50) = 1.0 nM) and selective CRF(1) receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.


Subject(s)
Pyrazines/pharmacology , Pyrazines/pharmacokinetics , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Humans , Inhibitory Concentration 50 , Male , Metabolic Clearance Rate , Pyrazines/chemistry , Pyrazines/metabolism , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism
15.
J Med Chem ; 52(14): 4173-91, 2009 Jul 23.
Article in English | MEDLINE | ID: mdl-19552437

ABSTRACT

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.


Subject(s)
Pyrazines/chemistry , Pyrazines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Cell Line, Tumor , Humans , Macaca fascicularis , Male , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
16.
Bioorg Med Chem Lett ; 18(1): 66-71, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18037290

ABSTRACT

The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Imidazolines/chemical synthesis , Imidazolines/chemistry , Imidazolines/pharmacology , Models, Molecular , Structure-Activity Relationship , Thiazoles/chemical synthesis
17.
J Med Chem ; 50(9): 2269-72, 2007 May 03.
Article in English | MEDLINE | ID: mdl-17402721

ABSTRACT

The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.


Subject(s)
Models, Molecular , Pteridines/chemical synthesis , Pyridazines/chemical synthesis , Quantitative Structure-Activity Relationship , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Choroid Plexus/metabolism , Frontal Lobe/metabolism , In Vitro Techniques , Pteridines/chemistry , Pteridines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Radioligand Assay , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Swine
18.
Org Lett ; 9(7): 1279-82, 2007 Mar 29.
Article in English | MEDLINE | ID: mdl-17338536

ABSTRACT

[structure: see text]. The first asymmetric synthesis of the (S)-1,1-dioxido-isothiazolidin-3-one ((S)-IZD) pTyr mimetic, which has been incorporated into the recently reported potent protein tyrosine phosphatase 1B (PTP1B) inhibitors, is presented herein. The key reaction is the reduction of the (R)-oxido-isothiazolidin-3-one heterocycle with excellent regiochemical and stereochemical control (>98% ee; 82% yield).


Subject(s)
Enzyme Inhibitors/chemical synthesis , Phosphotyrosine/chemistry , Thiazoles/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Models, Molecular , Molecular Mimicry , Molecular Structure , Protein Tyrosine Phosphatases/antagonists & inhibitors , Stereoisomerism , Thiazoles/chemistry , Thiazoles/pharmacology
19.
IDrugs ; 10(2): 112-5, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17285463

ABSTRACT

Biological targets that are challenging to pursue for medicinal chemists, such as the protein phosphatases, require creative and innovative approaches for identifying and optimizing previously unknown classes of inhibitors. To achieve these lofty objectives, medicinal chemists must utilize the latest computational, structural biology, synthetic and analytical technologies in the drug development process. The iterative use of structure-based drug design often plays a key role, as illustrated by the independent discoveries of two research groups involving the identification and optimization of protein tyrosine phosphatase 1B inhibitors that have novel heterocyclic phosphotyrosine mimetics. The newly designed pharmacophore provides a promising chemical lead for phosphatase drug discovery and a valuable chemical tool for phosphatase research in general.


Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Phosphoprotein Phosphatases/antagonists & inhibitors , Animals , Dopamine and cAMP-Regulated Phosphoprotein 32/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Humans , Molecular Mimicry , Structure-Activity Relationship
20.
Bioorg Med Chem Lett ; 17(3): 736-40, 2007 Feb 01.
Article in English | MEDLINE | ID: mdl-17097290

ABSTRACT

Benzothiazole benzimidazole (S)-isothiazolidinone ((S)-IZD) derivatives 5 were discovered through a peptidomimetic modification of the tripeptide (S)-IZD protein tyrosine phosphatase 1B (PTP1B) inhibitor 1. These derivatives are potent, competitive, and reversible inhibitors of PTP1B with improved caco-2 permeability. An X-ray co-crystal structure of inhibitor 5/PTP1B at 2.2A resolution demonstrated that the benzothiazole benzimidazole forms bi-dentate H-bonds to Asp48, and the benzothiazole interacts with the surface of the protein in a solvent exposed region towards the C-site. The design, synthesis, and SAR of this novel series of benzothiazole benzimidazole containing (S)-IZD inhibitors of PTP1B are presented herein.


Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Benzothiazoles/chemical synthesis , Benzothiazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Caco-2 Cells , Cell Membrane Permeability/drug effects , Humans , Models, Molecular , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...