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1.
J Pharm Sci ; 107(5): 1352-1360, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29317226

RESUMO

BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in preclinical studies in nonrodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients, and prototype formulations were developed. In vitro tests showed that fine/microemulsions were formed after aqueous dilution of lipid formulations, and BMS-A was transferred from oil phase to aqueous phase with enhanced solubility following lipid digestion. When dosed in dogs at 200 mg/kg, a Gelucire-based formulation exhibited more than 10-fold higher exposure compared to the solution formulation and was thus selected for toxicology studies in dogs. For monkeys, an olive oil formulation was developed, and the exposure was about 7-fold higher than that from the solution. In summary, lipid-based drug delivery could be applied in early stages of drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic compounds, while facilitating the candidate selection of a molecule which is more specifically designed for bioperformance in a lipid-based drug delivery strategy.

2.
Bioorg Med Chem Lett ; 26(14): 3278-3281, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27256912

RESUMO

Hydroxyl 1,2-diphenylethanamine analogs were identified as potent inhibitors of cholesterol ester transfer protein (CETP), a therapeutic target to raise HDL cholesterol. In an effort to improve the pharmaceutical properties in the previously disclosed DiPhenylPyridineEthanamine (DPPE) series, polar groups were introduced to the N-linked quaternary center. Optimization of analogues for potency, in vitro liability profile and efficacy led to identification of lead compound 16 which demonstrated robust pharmacodynamic effects in human CETP/apo-B100 dual transgenic mice.


Assuntos
Aminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Descoberta de Drogas , Aminas/síntese química , Aminas/química , Animais , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Relação Estrutura-Atividade
3.
J Med Chem ; 58(22): 9010-26, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26524347

RESUMO

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.


Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Benzilaminas/síntese química , Benzilaminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacocinética , Aterosclerose/tratamento farmacológico , Benzamidas/farmacocinética , Benzilaminas/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , HDL-Colesterol/sangue , Cricetinae , Citocromo P-450 CYP11B2/antagonistas & inibidores , Cães , Descoberta de Drogas , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley
4.
ACS Med Chem Lett ; 6(8): 908-12, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288692

RESUMO

BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.

7.
J Med Chem ; 55(13): 6162-75, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22650305

RESUMO

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.


Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Animais , Anticolesterolemiantes/síntese química , Apolipoproteína B-100/antagonistas & inibidores , Apolipoproteína B-100/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença das Coronárias/tratamento farmacológico , Cricetinae , Descoberta de Drogas , Frequência Cardíaca/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Ratos , Estilbenos/síntese química
8.
Ther Adv Med Oncol ; 3(1): 11-25, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21789152

RESUMO

Ixabepilone demonstrates marked synergistic activity in combination with capecitabine, which served as the rationale for the evaluation of this combination in the clinic. Ixabepilone plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer (MBC) progressing after treatment with an anthracycline and a taxane; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy. An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab, bevacizumab, brivanib, and cetuximab; with immune-modulating agents such as anti-CTLA-4 antibody; and with other chemotherapy drugs such as irinotecan and epirubicin. Notably, experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab-paclitaxel combined with bevacizumab. These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in HER2-positive breast cancer; with bevacizumab in breast cancer, endometrial cancer, renal cancer, and non-small cell lung cancer (NSCLC); with cetuximab in breast cancer, NSCLC, and pancreatic cancer; and with brivanib, dasatinib, sorafinib, sunitinib, or vorinostat in MBC. Preliminary results from several of these trials suggest that ixabepilone-based combinations have promising anticancer activity.

9.
Prostate ; 71(5): 480-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20878947

RESUMO

BACKGROUND: Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. METHODS: Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. RESULTS: As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. CONCLUSIONS: Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs.


Assuntos
Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/toxicidade , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/farmacocinética , Animais , Cães , Descoberta de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias da Próstata/metabolismo , Ratos , Ratos Sprague-Dawley
11.
Cancer Res ; 69(16): 6522-30, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19654297

RESUMO

Despite an excellent initial response to first-line hormonal treatment, most patients with metastatic prostate cancer will succumb to a hormone-refractory form of the disease. Because these tumors are still dependent on a functional androgen receptor (AR), there is a need to find novel and more potent antiandrogens. While searching for small molecules that bind to the AR and inhibit its transcriptional activity, BMS-641988 was discovered. This novel antiandrogen showed an increased (>1 log) potency compared with the standard antiandrogen, bicalutamide, in both binding affinity to the AR and inhibition of AR-mediated transactivation in cell-based reporter assays. In mature rats, BMS-641988 strongly inhibited androgen-dependent growth of the ventral prostate and seminal vesicles. In the CWR-22-BMSLD1 human prostate cancer xenograft model, BMS-641988 showed increased efficacy over bicalutamide (average percent tumor growth inhibition >90% versus <50%), even at exposure levels of bicalutamide 3-fold greater than what can be attained in humans. Furthermore, BMS-641988 was efficacious in CWR-22-BMSLD1 tumors initially refractory to treatment with bicalutamide. BMS-641988 was highly efficacious in the LuCaP 23.1 human prostate xenograft model, inducing stasis throughout the approximately 30-day dosing. To explore the functional mechanisms of BMS-641988, gene expression profiling analysis was done on CWR-22-BMSLD1 xenograft models in mice. Treatment with BMS-641988 resulted in a global gene expression profile more similar to castration compared with that of bicalutamide. Overall, these data highlight that the unique preclinical profile of BMS-641988 may provide additional understanding for the hormonal treatment of prostate cancer.


Assuntos
Antagonistas de Receptores de Andrógenos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Imidas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Imidas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Bioorg Med Chem Lett ; 18(6): 1910-5, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18291644

RESUMO

A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.


Assuntos
Antagonistas de Receptores de Andrógenos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Isoindóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão , Desenho de Drogas , Humanos , Isoindóis/síntese química , Isoindóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Nitrilos/farmacologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Ligação Proteica , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Compostos de Tosil/farmacologia , Células Tumorais Cultivadas
14.
Bioorg Med Chem Lett ; 18(2): 634-9, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18055203

RESUMO

2-Amino-5-(thioaryl)thiazoles are potent inhibitors of TrkA (e.g., 20h, TrkA IC(50)=0.6 nM) that show anti-proliferative effect in cellular assays. A proposed inhibitor binding mode to TrkA active site is consistent with key SAR observations.


Assuntos
Receptor trkA/antagonistas & inibidores , Tiazóis/farmacologia , Fosforilação , Receptor trkA/metabolismo , Relação Estrutura-Atividade , Tiazóis/química
15.
J Med Chem ; 49(26): 7596-9, 2006 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-17181141

RESUMO

A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidantoínas/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Receptores Androgênicos/metabolismo , Administração Oral , Animais , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Células Cultivadas , Di-Hidrotestosterona/farmacologia , Humanos , Hidantoínas/administração & dosagem , Hidantoínas/síntese química , Hidantoínas/química , Luciferases/metabolismo , Masculino , Camundongos , Músculo Esquelético/crescimento & desenvolvimento , Mioblastos/efeitos dos fármacos , Ratos , Ativação Transcricional
17.
Prostate ; 65(2): 159-70, 2005 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-15924334

RESUMO

BACKGROUND: Endocrine therapy of prostate cancer (PCa) relies on agents which disrupt the biosynthesis of testosterone in the testis and/or by direct antagonism of active hormone on the androgen receptor (AR) in non-gonadal target tissues of hormone action such as the prostate. METHODS: In an effort to evaluate new therapies which could inhibit gonadal or non-gonadal testosterone biosynthesis, we developed high throughput biochemical and cellular screening assays to identify inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3), the enzyme catalyzing the conversion of androstenedione (AdT) to testosterone. RESULTS: Initial screening efforts identified a natural product, 18beta-glycyrrhetinic acid, and a novel derivative of AdT, 3-O-benzylandrosterone, as potent inhibitors of the enzyme. Further efforts led to the identification of several classes of non-steroidal, low molecular weight compounds that potently inhibited 17beta-HSD3 enzymatic activity. One of the most potent classes of 17beta-HSD3 inhibitors was a series of anthranilamide small molecules identified from a collection of compounds related to non-steroidal modulators of nuclear hormone receptors. The anthranilamide based 17beta-HSD3 inhibitors were exemplified by BMS-856, a compound displaying low nanomolar inhibition of 17beta-HSD3 enzymatic activity. In addition, this series of compounds displayed potent inhibition of 17beta-HSD3-mediated cellular conversion of AdT to testosterone and inhibited the 17beta-HSD3-mediated conversion of testosterone necessary to promote AR-dependent transcription. CONCLUSIONS: The identification of non-steroidal functional inhibitors of 17beta-HSD3 may be a useful complementary approach for the disruption of testosterone biosynthesis in the treatment of PCa.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/fisiologia , Anti-Inflamatórios/farmacologia , Ácido Glicirretínico/farmacologia , Testosterona/biossíntese , ortoaminobenzoatos/farmacologia , Androstenodiona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico
18.
Bioorg Med Chem Lett ; 15(2): 271-6, 2005 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-15603938

RESUMO

A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.


Assuntos
Antagonistas de Androgênios/síntese química , Indóis/química , Antagonistas de Androgênios/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Indóis/farmacologia , Isoformas de Proteínas , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Bioorg Med Chem Lett ; 15(2): 389-93, 2005 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-15603960

RESUMO

A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.


Assuntos
Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Indóis/química , Animais , Humanos , Concentração Inibidora 50 , Masculino , Mutação , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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