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1.
Bioorg Med Chem Lett ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348490

RESUMO

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.

2.
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.

3.
J Org Chem ; 81(19): 9499-9506, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27615449

RESUMO

A one-step synthesis of Fmoc-protected aryl/heteroaryl-substituted phenylalanines (Bip derivatives) using the nonaqueous palladium-catalyzed Suzuki-Miyaura cross-coupling (SMC) reaction of Fmoc-protected bromo- or iodophenylalanines is reported. This protocol allows for the direct formation of a variety of unnatural biaryl-containing amino acids in good to excellent yield, which can be readily used in subsequent Fmoc solid-phase peptide synthesis. The synthetic utility of this method is also demonstrated by the SMC reaction of bromophenylalanine-containing tripeptides.

4.
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
5.
ChemMedChem ; 9(10): 2327-43, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24989964

RESUMO

Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.


Assuntos
Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ureia/análogos & derivados , Animais , Humanos , Espectroscopia de Ressonância Magnética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Espectrometria de Massas por Ionização por Electrospray , Ureia/farmacocinética , Ureia/farmacologia
6.
J Med Chem ; 57(14): 6150-64, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-24931384

RESUMO

Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y12 and P2Y1. Blocking P2Y12 receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y1 antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y12 inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y1 antagonist, 1. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y12 antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y1 antagonism as a promising new antiplatelet target.


Assuntos
Descoberta de Drogas , Indóis/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y1/metabolismo , Animais , Coagulação Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/química , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/química , Antagonistas do Receptor Purinérgico P2Y/síntese química , Antagonistas do Receptor Purinérgico P2Y/química , Coelhos , Ratos , Relação Estrutura-Atividade , Trombose/tratamento farmacológico
7.
Bioorg Med Chem Lett ; 24(11): 2481-5, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24767843

RESUMO

Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5 µM with 10 µM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.


Assuntos
Indóis/química , Piperidinas/química , Receptores Purinérgicos P2Y1/metabolismo , Tiadiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Indóis/administração & dosagem , Estrutura Molecular , Piperidinas/administração & dosagem , Ratos , Relação Estrutura-Atividade , Tiadiazóis/administração & dosagem , Tiadiazóis/química
8.
Bioorg Med Chem Lett ; 24(5): 1294-8, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24513044

RESUMO

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.


Assuntos
Compostos de Fenilureia/química , Inibidores da Agregação de Plaquetas/química , Antagonistas do Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Tiazóis/química , Ureia/análogos & derivados , Administração Oral , Animais , Cães , Meia-Vida , Macaca fascicularis , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Trombose/tratamento farmacológico , Ureia/farmacocinética , Ureia/farmacologia , Ureia/uso terapêutico
9.
J Med Chem ; 56(22): 9275-95, 2013 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-24164581

RESUMO

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.


Assuntos
Desenho de Drogas , Conformação Molecular , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Receptores Purinérgicos P2Y1/metabolismo , Compostos de Espiro/farmacologia , Compostos de Espiro/farmacocinética , Ureia/farmacologia , Ureia/farmacocinética , Animais , Disponibilidade Biológica , Humanos , Indóis/química , Modelos Moleculares , Compostos de Fenilureia/química , Compostos de Fenilureia/metabolismo , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y1/química , Homologia de Sequência de Aminoácidos , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Ureia/química , Ureia/metabolismo
10.
Bioorg Med Chem Lett ; 23(11): 3239-43, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23602442

RESUMO

Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.


Assuntos
Fibrinolíticos/química , Compostos de Fenilureia/química , Antagonistas do Receptor Purinérgico P2Y/química , Piridinas/química , Receptores Purinérgicos P2Y1/química , Ureia/química , Animais , Células CACO-2 , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/síntese química , Fibrinolíticos/farmacocinética , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Tempo de Tromboplastina Parcial , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Coelhos , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Solubilidade , Relação Estrutura-Atividade , Trombose/tratamento farmacológico , Ureia/farmacocinética , Ureia/uso terapêutico , Água/química
11.
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
12.
Org Lett ; 13(7): 1804-7, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21381681

RESUMO

The (hetero)aromatic trifluoromethyl group is present in many biologically active molecules and is generally considered to be chemically stable. In this paper, a convenient one-step synthesis of C-C linked aryl-heterocycles or heteroaryl-heterocycles in good to excellent yields via the reaction of anionically activated trifluoromethyl groups with amino nucleophiles containing a second NH, OH, or SH nucleophile in 1 N sodium hydroxide is reported. The method has high functional group tolerability and is potentially useful in parallel synthesis.


Assuntos
Compostos de Flúor/química , Compostos Heterocíclicos/química , Ânions/química , Metilação , Estrutura Molecular , Estereoisomerismo
14.
Bioorg Med Chem Lett ; 17(18): 5041-8, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17643988

RESUMO

We previously reported a series of enantiopure cis-(1R,2S)-cyclopentyldiamine derivatives as potent and selective inhibitors of Factor Xa (FXa). Herein, we describe our approach to improve the metabolic stability of this series via core modifications. Multiple resulting series of compounds demonstrated similarly high FXa potency and improved metabolic stability in human liver microsomes compared with the cyclopentyldiamide 1. (3R,4S)-Pyrrolidinyldiamide 31 was the best overall compound with human FXa K(i) of 0.50 nM, PT EC(2x) of 2.1 microM in human plasma, bioavailability of 25% and t(1/2)of 2.7h in dogs. Further biochemical characterization of compound 31 is also presented.


Assuntos
Inibidores do Fator Xa , Inibidores de Serino Proteinase/farmacologia , Animais , Disponibilidade Biológica , Cães , Meia-Vida , Humanos , Modelos Moleculares , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 17(16): 4419-27, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17588746

RESUMO

In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties.


Assuntos
Diaminas/química , Diaminas/farmacologia , Inibidores do Fator Xa , Anticoagulantes/química , Anticoagulantes/farmacologia , Sítios de Ligação , Humanos , Modelos Moleculares , Estrutura Molecular , Tempo de Protrombina , Relação Estrutura-Atividade , Difração de Raios X
16.
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.
Bioorg Med Chem Lett ; 12(21): 3183-6, 2002 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-12372529

RESUMO

A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.


Assuntos
Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/farmacologia , Trombina/antagonistas & inibidores , Animais , Sítios de Ligação/efeitos dos fármacos , Catálise , Humanos , Camundongos , Relação Estrutura-Atividade , Trombina/química , Trombina/toxicidade
18.
Bioorg Med Chem Lett ; 12(1): 41-4, 2002 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-11738569

RESUMO

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure- activity relationships (SAR), selectivity and activity in vivo. BMS-189090 (5) is identified as a potent, selective, and reversible inhibitor of human alpha-thrombin that is efficacious in vivo in a mice lethality model, and in inhibiting both arterial and venous thrombosis in a rat model.


Assuntos
Serina/análogos & derivados , Trombina/antagonistas & inibidores , Animais , Sítios de Ligação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/síntese química , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Camundongos , Ácidos Nipecóticos/síntese química , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacologia , Ratos , Serina/síntese química , Serina/química , Serina/farmacologia , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Trombina/química , Trombose/tratamento farmacológico , Trombose/prevenção & controle
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