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1.
Clin Cancer Res ; 23(24): 7584-7595, 2017 Dec 15.
Article in English | MEDLINE | ID: mdl-28972046

ABSTRACT

Purpose: PTEN-null tumors become dependent on the PI3Kß isoform and can be targeted by molecules such as the selective PI3Kß inhibitor AZD8186. However, beyond the modulation of the canonical PI3K pathway, the consequences of inhibiting PI3Kß are poorly defined.Experimental Design: To determine the broader impact of AZD8186 in PTEN-null tumors, we performed a genome-wide RNA-seq analysis of PTEN-null triple-negative breast tumor xenografts treated with AZD8186. Mechanistic consequences of AZD8186 treatment were examined across a number of PTEN-null cell lines and tumor models.Results: AZD8186 treatment resulted in modification of transcript and protein biomarkers associated with cell metabolism. We observed downregulation of cholesterol biosynthesis genes and upregulation of markers associated with metabolic stress. Downregulation of cholesterol biosynthesis proteins, such as HMGCS1, occurred in PTEN-null cell lines and tumor xenografts sensitive to AZD8186. Therapeutic inhibition of PI3Kß also upregulated PDHK4 and increased PDH phosphorylation, indicative of reduced carbon flux into the TCA cycle. Consistent with this, metabolomic analysis revealed a number of changes in key carbon pathways, nucleotide, and amino acid biosynthesis.Conclusions: This study identifies novel mechanistic biomarkers of PI3Kß inhibition in PTEN-null tumors supporting the concept that targeting PI3Kß may exploit a metabolic dependency that contributes to therapeutic benefit in inducing cell stress. Considering these additional pathways will guide biomarker and combination strategies for this class of agents. Clin Cancer Res; 23(24); 7584-95. ©2017 AACR.


Subject(s)
Aniline Compounds/administration & dosage , Chromones/administration & dosage , Class II Phosphatidylinositol 3-Kinases/genetics , PTEN Phosphohydrolase/genetics , Triple Negative Breast Neoplasms/drug therapy , Aniline Compounds/adverse effects , Animals , Cell Line, Tumor , Chromones/adverse effects , Female , Gene Expression Regulation, Neoplastic , Humans , Hydroxymethylglutaryl-CoA Synthase/genetics , Metabolic Networks and Pathways/genetics , Mice , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor Assays
2.
PLoS One ; 12(8): e0183048, 2017.
Article in English | MEDLINE | ID: mdl-28806782

ABSTRACT

BACKGROUND: The phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K α and δ isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development. It has been used widely with PI3K inhibitors both clinically and pre-clinically because of the role of the PI3K pathway in glucose metabolism. In this study we investigated the potential of 18F-FDG PET as a non-invasive pharmacodynamic biomarker for AZD8835. We sought to understand if 18F-FDG PET could determine the minimally effective dose of AZD8835 and correlate with other pharmacodynamic biomarkers for validation of its use in clinical development. 18F-FDG PET scans were performed in nude mice in the BT474C breast xenograft model. Mice were fasted prior to imaging and static 18F-FDG PET was performed. Treatment groups received AZD8835 by oral gavage at a dose volume of 10ml/kg. Treatment groups received either 3, 6, 12.5, 25 or 50mg/kg AZD8835. Tumour growth was monitored throughout the study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis was performed. RESULTS: Results showed that AZD8835 reduced 18F-FDG uptake at a dose of 12.5, 25 and 50mg/kg with no significant reduction at doses of 3 and 6mg/kg. These results were consistent with other pharmacodynamics biomarkers measured and show 18F-FDG PET as a sensitive biomarker with the ability to determine the minimal effective dose of AZD8835. CONCLUSIONS: Our pre-clinical studies support the use of 18F-FDG PET imaging as a sensitive and non- invasive pharmacodynamic biomarker (understanding the role of PI3K signalling in glucose uptake) for AZD8835 with a decrease in 18F-FDG uptake observed at only two hours post treatment. The decrease in 18F-FDG uptake was dose dependent and data showed excellent PK/PD correlation. This data supports and parallels observations obtained with this class of compounds in patients.


Subject(s)
Fluorodeoxyglucose F18/metabolism , Oxadiazoles/pharmacology , Oxadiazoles/pharmacokinetics , Phosphoinositide-3 Kinase Inhibitors , Piperidines/pharmacology , Piperidines/pharmacokinetics , Positron-Emission Tomography/methods , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Animals , Biomarkers, Tumor/metabolism , Blood Glucose/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Female , Gene Knockdown Techniques , Homeostasis/drug effects , Humans , Mice, Nude , Oxadiazoles/administration & dosage , Phosphatidylinositol 3-Kinases/metabolism , Piperidines/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
3.
Bioorg Med Chem Lett ; 27(13): 3030-3035, 2017 07 01.
Article in English | MEDLINE | ID: mdl-28526367

ABSTRACT

We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kß and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50mg/kg twice daily orally) in the MCF7 xenograft model in mice.


Subject(s)
Drug Discovery , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrazines/pharmacology , Class I Phosphatidylinositol 3-Kinases , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazines/chemical synthesis , Pyrazines/chemistry , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 27(9): 1949-1954, 2017 05 01.
Article in English | MEDLINE | ID: mdl-28347666

ABSTRACT

Attempts to lock the active conformation of compound 4, a PI3Kß/δ inhibitor (PI3Kß cell IC50 0.015µM), led to the discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3Kß/δ inhibitors. Compound 10 proved exquisitely potent and selective: PI3Kß cell IC50 0.0011µM in PTEN null MDA-MB-468 cell and PI3Kδ cell IC50 0.014µM in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3Kß/δ preclinical candidates.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Benzopyrans/chemistry , Benzopyrans/therapeutic use , PTEN Phosphohydrolase/genetics , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzopyrans/pharmacokinetics , Benzopyrans/pharmacology , Cell Line, Tumor , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Dogs , Gene Deletion , Humans , Male , Mice, Nude , Molecular Docking Simulation , Morpholinos/chemistry , Morpholinos/pharmacokinetics , Morpholinos/pharmacology , Morpholinos/therapeutic use , Prostate/drug effects , Prostate/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use
5.
EJNMMI Res ; 6(1): 62, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27515445

ABSTRACT

BACKGROUND: The phosphatidylinositol 3 kinase (PI3K) signalling pathway is frequently altered in human cancer and a promising therapeutic target. AZD8186 (AstraZeneca) is a PI3Kß/δ inhibitor, currently in phase 1 clinical trials. (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) is often used as a biomarker for inhibitors targeting the PI3K axis because of the association of this pathway with glucose metabolism. In this study, we assessed if (18)F-FDG PET could be used as a pharmacodynamic marker to monitor PI3Kß inhibition by AZD8186, and hence have potential as a clinical biomarker of PI3Kß pathway activation, and for patient selection. (18)F-FDG PET scans were performed in nude mice bearing 786-0 renal, U87-MG glioma, and BT474C breast xenograft models. Mice were fasted prior to imaging and static (18)F-FDG PET imaging was performed. Tumour growth was monitored throughout each study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis performed. RESULTS: Results showed that in PTEN null tumour xenograft models, 786-0 and U87-MG, the PI3Kß inhibitor AZD8186 reduces (18)F-FDG uptake at a dose of 50 mg/kg, the same dose which causes tumour inhibition, while it has no impact in a PI3Kα mutant tumour xenograft BT474C. Consistent with the change in (18)F-FDG uptake, AZD8186 also modulated AKT and associated glucose pathway biomarkers in the PTEN null tumour xenografts but not in PTEN wild-type tumours. CONCLUSIONS: Our pre-clinical studies support the use of (18)F-FDG PET imaging as a sensitive and non-invasive pharmacodynamic biomarker for use in clinical studies with AZD8186.

6.
Bioorg Med Chem Lett ; 26(9): 2318-23, 2016 May 01.
Article in English | MEDLINE | ID: mdl-26996374

ABSTRACT

We report the discovery and optimisation of a series of 8-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-2-morpholino-4-oxo-chromene-6-carboxamides, leading to compound 16 as a potent and selective PI3Kß/δ inhibitor: PI3Kß cell IC50 0.012 µM (in PTEN null MDA-MB-468 cell) and PI3Kδ cell IC50 0.047 µM (in Jeko-1 B-cell), with good pharmacokinetics and physical properties. In vivo, 16 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-deficient PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Compound 16 was selected as a preclinical candidate for the treatment of PTEN-deficient tumours.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Isoenzymes/antagonists & inhibitors , Morpholinos/chemistry , Morpholinos/pharmacology , PTEN Phosphohydrolase/genetics , Phosphoinositide-3 Kinase Inhibitors , Animals , Cell Line, Tumor , Humans , Mice , Phosphorylation
7.
Mol Cancer Ther ; 15(5): 877-89, 2016 05.
Article in English | MEDLINE | ID: mdl-26839307

ABSTRACT

The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Kα is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with a novel PI3K inhibitor, AZD8835, currently in phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Kα and PI3Kδ with selectivity versus PI3Kß, PI3Kγ, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor-positive (ER(+)) breast cancer cell lines BT474, MCF7, and T47D (sub-µmol/L GI50s). Consistent with this, AZD8835 demonstrated antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced antitumor activity (up to 92% regression). Combination partners were prioritized on the basis of our mechanistic insights demonstrating signaling pathway cross-talk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER(+) breast cancer patients. In summary, AZD8835 IHDS delivers strong antitumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation. Mol Cancer Ther; 15(5); 877-89. ©2016 AACR.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/metabolism , Oxadiazoles/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Piperidines/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cluster Analysis , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Gene Expression Profiling , Humans , Isoenzymes , Mice , Oxadiazoles/chemistry , Piperidines/chemistry , Xenograft Model Antitumor Assays
8.
Bioorg Med Chem Lett ; 25(22): 5155-62, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26475521

ABSTRACT

Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kß and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.


Subject(s)
Antineoplastic Agents/pharmacology , Oxadiazoles/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Dogs , Humans , Mice , Mice, Nude , Mice, SCID , Molecular Docking Simulation , Oxadiazoles/chemical synthesis , Piperidines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Xenograft Model Antitumor Assays
9.
Mol Cancer Ther ; 14(1): 48-58, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25398829

ABSTRACT

Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kß isoform. Inhibitors of PI3Kß have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kß and PI3Kδ (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI50 < 1 µmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kß with activity against PI3Kδ signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.


Subject(s)
Aniline Compounds/administration & dosage , Antineoplastic Agents/administration & dosage , Chromones/administration & dosage , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms/drug therapy , Signal Transduction/drug effects , Taxoids/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cell Line, Tumor , Cell Proliferation/drug effects , Chromones/pharmacology , Docetaxel , Drug Synergism , Female , Humans , Male , Mice , PTEN Phosphohydrolase/deficiency , Prostatic Neoplasms/metabolism , Triple Negative Breast Neoplasms/metabolism , Xenograft Model Antitumor Assays
10.
J Med Chem ; 58(2): 943-62, 2015 Jan 22.
Article in English | MEDLINE | ID: mdl-25514658

ABSTRACT

Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kß activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kß/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.


Subject(s)
Aniline Compounds/chemical synthesis , Chromones/chemical synthesis , Neoplasms, Experimental/drug therapy , PTEN Phosphohydrolase/deficiency , Phosphoinositide-3 Kinase Inhibitors , Aniline Compounds/pharmacology , Animals , Chromones/pharmacology , Dogs , Drug Discovery , Humans , Male , Mice , Neoplasms, Experimental/chemistry , Structure-Activity Relationship
11.
Cancer Cell ; 27(1): 109-22, 2015 Jan 12.
Article in English | MEDLINE | ID: mdl-25544636

ABSTRACT

In PTEN-mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kß. A selective inhibitor of PI3Kß inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kß only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kß. In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions.


Subject(s)
Aniline Compounds/pharmacology , Chromones/pharmacology , Neoplasms/drug therapy , PTEN Phosphohydrolase/genetics , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Thiazoles/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Neoplasm Transplantation , Neoplasms/genetics , Neoplasms/pathology , Signal Transduction/drug effects
12.
Bioorg Med Chem Lett ; 24(16): 3928-35, 2014 Aug 15.
Article in English | MEDLINE | ID: mdl-24992874

ABSTRACT

Starting from TGX-221, we designed a series of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as potent and selective PI3Kß/δ inhibitors. Structure-activity relationships and structure-property relationships around the aniline and the amide substituents are discussed. We identified compounds 17 and 18, which showed profound pharmacodynamic modulation of phosphorylated Akt in the PC3 prostate tumour xenograft, after a single oral dose. Compound 17 also gave significant inhibition of tumour growth in the PC3 prostate tumour xenograft model after chronic oral dosing.


Subject(s)
Amides/pharmacology , Antineoplastic Agents/pharmacology , Drug Discovery , Neoplasms, Experimental/drug therapy , PTEN Phosphohydrolase/deficiency , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Amides/administration & dosage , Amides/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Molecular Structure , Neoplasms, Experimental/enzymology , Neoplasms, Experimental/pathology , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship
13.
Bioorg Med Chem Lett ; 21(18): 5442-5, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21782422

ABSTRACT

Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.


Subject(s)
Prostatic Neoplasms/drug therapy , Pyridazines/pharmacology , Receptors, Androgen/metabolism , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Humans , Ligands , Male , Models, Molecular , Molecular Structure , Molecular Weight , Prostatic Neoplasms/metabolism , Pyridazines/chemical synthesis , Pyridazines/chemistry , Stereoisomerism , Structure-Activity Relationship
14.
Bioorg Med Chem Lett ; 17(23): 6448-54, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17937987

ABSTRACT

A new class of small-molecule GnRH antagonists, the thieno[2,3-b]pyrroles, was designed. Herein, the synthesis and structure-activity relationships are described. Substitution at the C4 position was investigated; during this study, it was observed that introducing piperazines and piperidines improved the physical properties of the compounds while retaining good in vitro potency. This exploration led to the discovery of amidopiperidines with improved pharmacokinetic properties.


Subject(s)
Pyrroles/chemical synthesis , Receptors, LHRH/antagonists & inhibitors , Thiophenes/chemical synthesis , Animals , Humans , Pyrroles/pharmacology , Rats , Receptors, LHRH/metabolism , Receptors, LHRH/physiology , Structure-Activity Relationship , Thiophenes/pharmacology
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