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1.
Bioorg Med Chem Lett ; 81: 129126, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36632927

RESUMO

A synthesis of 2'-fluoro and 2'-methoxy N6-methyladenosine phosphoramidites and their successful incorporation into oligonucleotides is reported. 2'-fluoro and 2́-methoxy modifications of sugars in siRNAs are known to aid stability and N6-methylation modifies the potency of therapeutic silencing RNAs (siRNA). We demonstrate that a combination of those modifications incorporated into the antisense strand of siRNA leads to efficient knockdown of a target gene in cells. This work broadens the available pool of chemical modifications of therapeutic siRNAs and provides tools for their efficient synthesis.


Assuntos
Compostos Organofosforados , RNA Interferente Pequeno/metabolismo , Metilação
2.
Chembiochem ; 22(3): 491-495, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-32936508

RESUMO

The introduction of N6-methyladenosine (m6 A) into siRNA targeting Factor VII impacts its potency in cells and has a significant influence on the selectivity of siRNA, including reduced off-targeting. These effects are dependent on the position of m6 A in the siRNA duplex, with some of the sequences identified as more potent and/or selective than their non-methylated counterpart. These findings broaden the repertoire of available chemical modifications for siRNA therapeutics and imply potential regulatory role of N6-methyladenosine in the RNAi pathways.


Assuntos
Adenosina/análogos & derivados , RNA Interferente Pequeno/química , Adenosina/química , Adenosina/genética , Epigênese Genética/genética , Conformação de Ácido Nucleico , RNA Interferente Pequeno/genética
3.
J Chem Inf Model ; 61(12): 5893-5905, 2021 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-34817173

RESUMO

OX1 receptor antagonists are of interest to treat, for example, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects. Herein, we describe the design of highly selective OX1 receptor antagonists driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2 receptor antagonist. Moderately selective OX1 antagonists comprising a [2.2.1]-bicyclic scaffold served as our starting point. Based on our binding mode hypothesis, we postulated which part of the scaffold points toward one of the regions where the two binding pockets differ. Structural changes in this part resulted in a modified core with higher inherent selectivity compared to the [2.2.1]-bicyclic template. The structure-based design, synthesis, and hit-to-lead evaluation of this novel OX1 receptor-selective scaffold are discussed herein.


Assuntos
Orexinas , Receptores de Orexina/metabolismo
5.
Bioorg Med Chem Lett ; 25(3): 575-80, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25556098

RESUMO

Computer-aided drug design scaffold hopping strategies were utilized to identify new classes of CB2 agonists when compounds of an established series with low nanomolar potency were challenging to optimize for good drug-like properties. Use of ligand-based design strategies through BI Builder (a tool for de novo design) and PharmShape (a virtual screening software package) approaches led to the discovery of new chemotypes. Specifically, compounds containing azetidine-, proline-, and piperidine-based cores were found to have low nanomolar and picomolar CB2 agonist activities with drug-like properties considered appropriate for early profiling.


Assuntos
Desenho de Fármacos , Receptor CB2 de Canabinoide/agonistas , Desenho Assistido por Computador , Humanos , Ligantes , Microssomos Hepáticos/metabolismo , Ligação Proteica , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 25(3): 581-6, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25556092

RESUMO

Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.


Assuntos
Isoxazóis/química , Prolina/química , Ácido Pirrolidonocarboxílico/análogos & derivados , Receptor CB2 de Canabinoide/agonistas , Animais , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Meia-Vida , Humanos , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Ligantes , Masculino , Microssomos Hepáticos/metabolismo , Prolina/farmacocinética , Prolina/uso terapêutico , Ligação Proteica , Ácido Pirrolidonocarboxílico/química , Ácido Pirrolidonocarboxílico/farmacocinética , Ácido Pirrolidonocarboxílico/uso terapêutico , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 25(3): 587-92, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25575658

RESUMO

A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.


Assuntos
Ácidos Pipecólicos/química , Piperidinas/química , Receptor CB2 de Canabinoide/agonistas , Tiazinas/química , Animais , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Meia-Vida , Humanos , Ligantes , Masculino , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Ácidos Pipecólicos/farmacocinética , Ácidos Pipecólicos/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ligação Proteica , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-Atividade , Tiazinas/farmacocinética , Tiazinas/uso terapêutico
8.
Bioorg Med Chem Lett ; 24(8): 1934-40, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24656565

RESUMO

Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.


Assuntos
Descoberta de Drogas , Glucocorticoides/síntese química , Metanol/química , Receptores de Glucocorticoides/agonistas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artrite/tratamento farmacológico , Sítios de Ligação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glucocorticoides/química , Glucocorticoides/farmacologia , Humanos , Concentração Inibidora 50 , Metanol/síntese química , Metanol/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Prednisolona/química , Prednisolona/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
9.
J Med Chem ; 66(4): 2832-2850, 2023 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-36727857

RESUMO

Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor BI-3231. Through high-throughput screening (HTS), using estradiol as substrate, compound 1 was identified and selected for subsequent optimization resulting in compound 45 (BI-3231). In addition to the characterization of compound 45 for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD+ dependency was investigated. To support Open Science, the chemical HSD17B13 probe BI-3231 will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.


Assuntos
Estudo de Associação Genômica Ampla , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ensaios de Triagem em Larga Escala
10.
Bioorg Med Chem Lett ; 21(14): 4276-80, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21689933

RESUMO

A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability.


Assuntos
Azepinas/química , Receptor CB2 de Canabinoide/agonistas , Azepinas/farmacologia , Células CACO-2 , Permeabilidade da Membrana Celular , Ensaios de Triagem em Larga Escala , Humanos , Microssomos Hepáticos/metabolismo , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 21(7): 2011-6, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21354795

RESUMO

A high-throughput screening campaign has identified 1,4-diazepane compounds which are potent Cannabinoid receptor 2 agonists with excellent selectivity against the Cannabinoid receptor 1. This class of compounds suffered from low metabolic stability. Following various strategies, compounds with a good stability in liver microsomes and rat PK profile have been identified.


Assuntos
Azepinas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Animais , Azepinas/química , Microssomos Hepáticos/metabolismo , Ratos , Ratos Wistar
12.
Org Lett ; 23(17): 6735-6739, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34424724

RESUMO

We report a synthesis of a carbocyclic, abasic RNA phosphoramidite decorated with an amino functionality. The building block was efficiently incorporated into an RNA oligonucleotide in a site-specific manner, followed by deprotection to a free amino group. The amino moiety could be further derivatized as exemplified with fluorescein N-hydroxysuccinimide ester. Hence, this convertible building block may provide access to a variety of RNA oligonucleotides via postsynthetic amino group functionalization. In particular, providing a vector toward nucleobase replacements.


Assuntos
Oligonucleotídeos/síntese química , Compostos Organofosforados/química , RNA/síntese química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oligonucleotídeos/química , RNA/química
13.
Bioorg Med Chem Lett ; 19(6): 1604-9, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19243942

RESUMO

Identification and optimization of two classes of CB2 selective agonists are described. A representative from each class is profiled in a murine model of inflammation and each shows similar efficacy to prednisolone upon oral dosing.


Assuntos
Morfolinas/síntese química , Receptor CB2 de Canabinoide/agonistas , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Inflamação , Camundongos , Modelos Químicos , Estrutura Molecular , Morfolinas/farmacologia , Receptor CB2 de Canabinoide/química , Estereoisomerismo
14.
Bioorg Med Chem Lett ; 19(6): 1588-91, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19246196

RESUMO

Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described.


Assuntos
Benzimidazóis/síntese química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Benzimidazóis/farmacologia , Complexo CD3/biossíntese , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 18(5): 1725-9, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18255291

RESUMO

A high-throughput screening campaign resulted in the discovery of a highly potent dual cannabinoid receptor 1 (CB1) and 2 (CB2) agonist. Following a thorough SAR exploration, a series of selective CB2 full agonists were identified.


Assuntos
Receptor CB2 de Canabinoide/agonistas , Estrutura Molecular , Receptor CB1 de Canabinoide/agonistas , Relação Estrutura-Atividade
16.
J Med Chem ; 58(4): 1669-90, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25671290

RESUMO

The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.


Assuntos
Acetamidas/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Descoberta de Drogas , Inibidores de Lipoxigenase/farmacologia , Oxidiazóis/farmacologia , Acetamidas/síntese química , Acetamidas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Modelos Moleculares , Conformação Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade
17.
ACS Med Chem Lett ; 5(12): 1318-23, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25516791

RESUMO

A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39.

18.
J Med Chem ; 57(4): 1583-98, 2014 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-24506830

RESUMO

Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.


Assuntos
Osso e Ossos/efeitos dos fármacos , Receptores de Glucocorticoides/agonistas , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Relação Estrutura-Atividade
19.
Expert Opin Ther Pat ; 22(5): 495-510, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22537079

RESUMO

INTRODUCTION: The activation of the cannabinoid receptor 2 (CB2) affects a myriad of immune responses from inflammation to neuroprotection, demonstrates analgesic effects and suppresses responses in many animal models of pain. Questions around the involvement of CB1 activation in these effects remain, but efforts have been directed toward the discovery of highly selective CB2 modulators lacking the psychotropic effects of cannabinoids, which are mediated by the CB1 receptor. AREAS COVERED: This review covers the patent literature which was published since April 2009 on CB2 selective modulators. It provides a general summary of the CB2 biology supporting the interest in CB2 as a drug target, new potential therapeutic indications and the development status of selective CB2 agonists. EXPERT OPINION: There is a continuous interest in the CB2 receptor as a drug target. Many highly selective compounds of various chemotypes have been identified and their analgesic effects in animal models further support the potential of this mechanism in pain therapy. Several companies have initiated clinical trials. While some of these have been terminated for various reasons, one can anticipate the emergence of new drugs from CB2 modulation once a better understanding around the cannabinoid receptors is gained.


Assuntos
Fatores Imunológicos/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Desenho de Fármacos , Humanos , Fatores Imunológicos/química , Legislação de Medicamentos , Estrutura Molecular , Patentes como Assunto , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
20.
J Med Chem ; 53(18): 6681-98, 2010 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-20735001

RESUMO

Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Piridinas/síntese química , Pirróis/síntese química , Receptores de Glucocorticoides/agonistas , Esteroides/química , Tecido Adiposo/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Aromatase/biossíntese , Aromatase/genética , Inibidores da Aromatase/farmacologia , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Células Cultivadas , Indução Enzimática , Feminino , Humanos , Ligação de Hidrogênio , Insulina/sangue , Interleucina-1/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Piridinas/efeitos adversos , Piridinas/farmacologia , Pirróis/efeitos adversos , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional
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