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1.
Angew Chem Int Ed Engl ; 57(50): 16302-16307, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30288907

RESUMO

YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.


Assuntos
Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/química , Bibliotecas de Moléculas Pequenas/química , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/química , Cristalografia por Raios X , Histonas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Domínios Proteicos , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/metabolismo
2.
Front Chem ; 6: 206, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29998095

RESUMO

Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease.

3.
Bioorg Med Chem ; 26(11): 2965-2972, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29567296

RESUMO

The polyadenosine-diphosphate-ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.


Assuntos
Cisteína Endopeptidases/química , Descoberta de Drogas , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Poli(ADP-Ribose) Polimerases/química , Regulação Alostérica , Carbazóis/química , Humanos , Concentração Inibidora 50 , Modelos Biológicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Relação Estrutura-Atividade
4.
J Med Chem ; 61(10): 4283-4289, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29140691

RESUMO

Tackling PPIs, particularly by stabilizing clinically favored conformations of target proteins, with orally available, bona fide small molecules remains a significant but immensely worthwhile challenge for the pharmaceutical industry. Success may be more likely through the application of nature's learnings to build intrinsic rigidity into the design of clinical candidates.


Assuntos
Desenho de Fármacos , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Descoberta de Drogas , Humanos , Ligação Proteica , Bibliotecas de Moléculas Pequenas/química
5.
Angew Chem Int Ed Engl ; 56(3): 827-831, 2017 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-27966810

RESUMO

The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.


Assuntos
Compostos Azo/farmacologia , Descoberta de Drogas , Hidralazina/farmacologia , Sondas Moleculares/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Compostos Azo/síntese química , Compostos Azo/química , Relação Dose-Resposta a Droga , Hidralazina/síntese química , Hidralazina/química , Sondas Moleculares/síntese química , Sondas Moleculares/química , Estrutura Molecular , Relação Estrutura-Atividade
6.
Bioorg Med Chem ; 24(21): 5462-5480, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27658798

RESUMO

Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure-activity-relationships. Several compounds blocked human and rat A1 and A2AARs at similar concentrations representing dual A1/A2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Ki human A1: 65.5nM, A2A: 230nM; Ki rat A1: 352nM, A2A: 316nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Ki human A1: 642nM, A2A: 203nM; Ki rat A1: 166nM, A2A: 121nM). Compound 57 was found to be well water-soluble (0.7mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1 and A2AARs and at MAO-B (Ki human A1: 393nM, human A2A: 595nM, IC50 human MAO-B: 210nM) thus allowing future in vivo explorations of the intended multi-target approach.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Purinas/farmacologia , Pirazinas/farmacologia , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Purinas/síntese química , Purinas/química , Pirazinas/síntese química , Pirazinas/química , Ratos , Solubilidade , Relação Estrutura-Atividade , Água/química
7.
J Med Chem ; 57(24): 10424-42, 2014 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-25431977

RESUMO

The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.


Assuntos
Ácidos Carboxílicos/química , Compostos Heterocíclicos/química , Imunossupressores/farmacologia , Imunossupressores/farmacocinética , Linfócitos/efeitos dos fármacos , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células Cultivadas , Imunossupressores/síntese química , Linfócitos/citologia , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
8.
ChemMedChem ; 9(8): 1704-24, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24817533

RESUMO

8-Benzyl-substituted tetrahydropyrazino[2,1-f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual-target-directed A1 /A2A adenosine receptor antagonists were identified. Several compounds showed triple-target inhibition; one of the best compounds was 8-(2,4-dichloro-5-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (72) (human AR: Ki  A1 217 nM, A2A 233 nM; IC50 MAO-B: 508 nM). Dichlorinated compound 36 [8-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione] was found to be the best triple-target drug in rat (Ki  A1 351 nM, A2A 322 nm; IC50 MAO-B: 260 nM), and may serve as a useful tool for preclinical proof-of-principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease-modifying treatment of neurodegenerative diseases are expected to show advantages over single-target therapeutics.


Assuntos
Inibidores da Monoaminoxidase/química , Xantinas/química , Animais , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacocinética , Inibidores da Monoaminoxidase/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Ratos , Solubilidade , Relação Estrutura-Atividade , Água/química , Xantinas/farmacocinética , Xantinas/uso terapêutico
9.
J Med Chem ; 56(11): 4580-96, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23631427

RESUMO

Blockade of A2A adenosine receptors (A2AARs) and inhibition of monoamine oxidase B (MAO-B) in the brain are considered attractive strategies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD). In the present study, benzothiazinones, e.g., 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide (13), were identified as a novel class of potent MAO-B inhibitors (IC50 human MAO-B: 1.63 nM). Benzothiazinones with large substituents in the 2-position, e.g., methoxycinnamoylamino, phenylbutyrylamino, or chlorobenzylpiperazinylbenzamido residues (14, 17, 27, and 28), showed high affinity and selectivity for A2AARs (Ki human A2AAR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A2AAR/MAO-B inhibitors with a nonxanthine structure were developed. The best derivative was N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide (17, Ki human A2A, 39.5 nM; IC50 human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A2AAR-induced cAMP accumulation and showed competitive, reversible MAO-B inhibition. The new compounds may be useful tools for validating the A2AAR/MAO-B dual target approach in PD.


Assuntos
Antagonistas do Receptor A2 de Adenosina/síntese química , Benzotiadiazinas/síntese química , Inibidores da Monoaminoxidase/síntese química , Fenilbutiratos/síntese química , Receptor A2A de Adenosina/metabolismo , Tiazinas/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Benzotiadiazinas/química , Benzotiadiazinas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Humanos , Técnicas In Vitro , Isoenzimas/antagonistas & inibidores , Fígado/efeitos dos fármacos , Fígado/enzimologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Fenilbutiratos/química , Fenilbutiratos/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia
10.
West J Emerg Med ; 13(1): 125-6, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22461945
11.
Bioorg Med Chem Lett ; 21(22): 6899-904, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21974957

RESUMO

During the lead optimization of NK(1)/NK(3) receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK(1) and NK(3) receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK(1)/NK(3) activity, were reported in this paper.


Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Lactamas/química , Lactamas/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-3/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Humanos , Modelos Moleculares , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-3/metabolismo , Relação Estrutura-Atividade
12.
Chemistry ; 15(12): 2874-914, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19204960

RESUMO

For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.


Assuntos
Antineoplásicos/síntese química , Produtos Biológicos/síntese química , Imunossupressores/síntese química , Sirolimo/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ciclização , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Estrutura Molecular , Sirolimo/química , Sirolimo/farmacologia
13.
J Med Chem ; 52(3): 818-25, 2009 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-19146417

RESUMO

The novel 7-transmembrane receptor MrgX1 is located predominantly in the dorsal root ganglion and has consequently been implicated in the perception of pain. Here we describe the discovery and optimization of a small molecule agonist and initial docking studies of this ligand into the receptor in order to provide a suitable lead and tool compound for the elucidation of the physiological function of the receptor.


Assuntos
Piperazinas/síntese química , Piridazinas/síntese química , Receptores Acoplados a Proteínas G/agonistas , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Cálcio/metabolismo , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Piperazinas/farmacologia , Piridazinas/farmacologia , Receptores Acoplados a Proteínas G/fisiologia , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 19(3): 990-4, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19095447

RESUMO

A novel oxytocin antagonist was identified by 'scaffold-hopping' using Cresset FieldScreen molecular field similarity searching. A single cycle of optimization driven by an understanding of the key pharmacophoric elements required for activity led to the discovery of a potent, selective and highly ligand-efficient oxytocin receptor antagonist. Selectivity over vasopressin receptors was rationalized based on differences in the structure of the natural ligands.


Assuntos
Desenho de Fármacos , Ocitocina/química , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Vasopressinas/química , Vasopressinas/química , Química Farmacêutica/métodos , Feminino , Humanos , Cinética , Ligantes , Modelos Químicos , Conformação Molecular , Trabalho de Parto Prematuro/tratamento farmacológico , Gravidez , Vasotocina/análogos & derivados , Vasotocina/química
15.
Bioorg Med Chem Lett ; 19(2): 528-32, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19081251

RESUMO

The optimisation of a tertiary sulfonamide high-throughput screening hit is described. A combination of high-throughput chemistry, pharmacophore analysis and in silico PK profiling resulted in the discovery of potent sulfonamide oxytocin receptor antagonists with oral exposure and good selectivity over vasopressin receptors.


Assuntos
Descoberta de Drogas , Ocitocina/antagonistas & inibidores , Sulfonamidas/farmacologia , Administração Oral , Modelos Moleculares , Sulfonamidas/administração & dosagem , Sulfonamidas/química
16.
Cal J Emerg Med ; 6(3): 52-4, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20847863

RESUMO

Non-traumatic abdominal pain is a common presenting complaint in emergency department (ED) patients, quoted in some contemporary literature as being the third most frequent reason for ED visits. We present the ED and hospital course of an unusual case of an 11 year old female with right lower quadrant abdominal pain. The admission assessment of this patient was "possible appendicitis versus gastroenteritis"; however, laparatomy revealed a right adnexal torsion. The need for emergency medicine physicians to always include gynecologic and other less common causes in the differential diagnosis and workup of abdominal pain in children is emphasized.

17.
J Med Chem ; 45(5): 999-1001, 2002 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-11855979

RESUMO

Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fibronectinas/biossíntese , Fibronectinas/genética , Humanos , Imidazóis/química , Imidazóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Serina-Treonina Quinases , RNA Mensageiro/biossíntese , Receptor do Fator de Crescimento Transformador beta Tipo I , Proteína Smad3 , Relação Estrutura-Atividade , Transativadores/metabolismo , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por Mitógeno
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