Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 60(14): 6166-6190, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28635286

RESUMO

Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.


Assuntos
Arginina/análogos & derivados , Flavonas/química , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Arginina/síntese química , Arginina/química , Arginina/farmacologia , Encéfalo/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Comportamento Alimentar/efeitos dos fármacos , Flavonas/síntese química , Flavonas/farmacologia , Células HEK293 , Humanos , Masculino , Membranas Artificiais , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Mutação , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/genética , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Relação Estrutura-Atividade
2.
J Med Chem ; 57(18): 7499-508, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25208139

RESUMO

G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic ß-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.


Assuntos
Descoberta de Drogas , Hipoglicemiantes/farmacologia , Terapia de Alvo Molecular , Piridonas/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Sulfonas/farmacologia , Animais , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Drogas , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Masculino , Camundongos , Modelos Moleculares , Conformação Proteica , Piridonas/química , Piridonas/farmacocinética , Piridonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/química , Sulfonas/química , Sulfonas/farmacocinética , Sulfonas/uso terapêutico
3.
Bioorg Med Chem Lett ; 24(11): 2539-45, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24755425

RESUMO

Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.


Assuntos
Benzofuranos/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Benzofuranos/síntese química , Benzofuranos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
4.
Future Med Chem ; 2(12): 1761-75, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21428799

RESUMO

Ever since the observation of late-onset obesity during the phenotypic characterization of the 5-HT(2C) knock-out mouse, the serotonin 5-HT(2C) receptor has been a drug target for obesity. Small-molecule agonists have repeatedly been shown to reduce food intake and body weight in rodent models of obesity. To date, however, only one compound, lorcaserin, has completed Phase III trials and currently awaits an US FDA decision following a negative advisory committee meeting. Agonist selectivity versus the highly homologous 5-HT(2A) and 5-HT(2B) receptors remains a significant hurdle. Ideally, a specific 5-HT(2C) agonist (completely devoid of 5-HT(2A) and 5-HT(2B) activity) would be preferred. The requirement of a basic amine coupled with larger, often aromatic, hydrophobic domains, to gain selectivity, often leads to additional challenges associated with cationic amphiphilic molecules such as hERG-channel inhibition and phospholipidosis. The success of future 5-HT(2C) agonists will depend on further improvements in selectivity (or attainment of complete specificity) and pharmaceutical properties to permit greater and sustained receptor stimulation, while avoiding side effects associated with the activation of other 5-HT receptors.


Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Benzazepinas/uso terapêutico , Obesidade/tratamento farmacológico , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Sequência de Aminoácidos , Animais , Fármacos Antiobesidade/farmacologia , Benzazepinas/química , Benzazepinas/farmacologia , Peso Corporal/efeitos dos fármacos , Descoberta de Drogas/tendências , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Dados de Sequência Molecular , Obesidade/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia
5.
Mol Pharmacol ; 76(6): 1211-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19767451

RESUMO

Successful development of 5-HT(2C) agonists requires selectivity versus the highly homologous 5-HT(2A) receptor, because agonism at this receptor can result in significant adverse events. (R)-9-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (compound 1) is a potent 5-HT(2C) agonist exhibiting selectivity over the human 5-HT(2A) receptor. Evaluation of the compound at the rat 5-HT(2A) receptor, however, revealed potent binding and agonist functional activity. The physiological consequence of this higher potency was the observation of a significant increase in blood pressure in conscious telemeterized rats that could be prevented by ketanserin. Docking of compound 1 in a homology model of the 5-HT(2A) receptor indicated a possible binding mode in which the ethyl group at the 9-position of the molecule was oriented toward position 5.46 of the 5-HT(2A) receptor. Within the human 5-HT(2A) receptor, position 5.46 is Ser242; however, in the rat 5-HT(2A) receptor, it is Ala242, suggesting that the potent functional activity in this species resulted from the absence of the steric bulk provided by the -OH moiety of the Ser in the human isoform. We confirmed this hypothesis using site-directed mutagenesis through the mutation of both the human receptor Ser242 to Ala and the rat receptor Ala242 to Ser, followed by radioligand binding and second messenger studies. In addition, we attempted to define the space allowed by the alanine by evaluating compounds with larger substitutions at the 9-position. The data indicate that position 5.46 contributed to the species difference in 5-HT(2A) receptor potency observed for a pyrazinoisoindolone compound, resulting in the observation of a significant cardiovascular safety signal.


Assuntos
Isoindóis/farmacologia , Pirazinas/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina , Animais , Ligação Competitiva/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular , Cães , Variação Genética , Humanos , Isoindóis/metabolismo , Ketanserina/farmacologia , Macaca fascicularis , Masculino , Atividade Motora/efeitos dos fármacos , Mutagênese Sítio-Dirigida , Ligação Proteica/efeitos dos fármacos , Pirazinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/genética , Receptor 5-HT2C de Serotonina/fisiologia , Homologia de Sequência de Aminoácidos , Antagonistas da Serotonina/farmacologia , Especificidade da Espécie , Homologia Estrutural de Proteína
6.
Curr Opin Drug Discov Devel ; 11(4): 438-45, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18600561

RESUMO

The serotonin 5-HT2C receptor is a G-protein-coupled receptor and is one of the 14 subtypes that constitutes the serotonin receptor family. Agonists of 5-HT2C have been implicated as potential treatments for diseases of significant unmet medical need, including obesity and schizophrenia. Despite approximately 10 years of discovery efforts, 5-HT2C agonists have only recently advanced into the clinic, likely because many of the early drug discovery efforts experienced significant difficulties with attaining receptor selectivity. Several of these issues related to receptor selectivity have now been overcome, resulting in the entry of compounds into advanced clinical trials. This review summarizes the progress in 5-HT2C agonist discovery and clinical development over the last 3 years. [sw1]what are the several issues - several issues relating to receptor selectivity?


Assuntos
Fármacos Antiobesidade/farmacologia , Antipsicóticos/farmacologia , Desenho de Drogas , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Antipsicóticos/química , Antipsicóticos/uso terapêutico , Benzazepinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/uso terapêutico , Resultado do Tratamento
7.
Bioorg Med Chem Lett ; 18(2): 749-54, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18054227

RESUMO

Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conversion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyrazole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of razaxaban and improved selectivity over thrombin.


Assuntos
Inibidores do Fator Xa , Pirazóis/química , Pirazóis/farmacologia , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacologia , Animais , Células CACO-2 , Cães , Humanos , Pirazóis/farmacocinética , Inibidores de Serino Proteinase/farmacocinética , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 18(2): 576-85, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18096386

RESUMO

Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.


Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Piperidinas/farmacologia , Receptores CCR3/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Animais , Inibidores das Enzimas do Citocromo P-450 , Cães , Eosinófilos/citologia , Ligações de Hidrogênio , Camundongos , Conformação Molecular , Piperidinas/química , Piperidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacocinética , Ureia/farmacologia
9.
Bioorg Med Chem Lett ; 17(23): 6481-8, 2007 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17933529

RESUMO

A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban.


Assuntos
Antitrombina III/síntese química , Antitrombina III/farmacocinética , Inibidores do Fator Xa , Indóis/química , Indóis/farmacocinética , Pirazóis/síntese química , Pirazóis/farmacocinética , Antitrombina III/metabolismo , Antitrombina III/farmacologia , Células CACO-2 , Desenho de Drogas , Humanos , Indóis/farmacologia , Ligação Proteica , Pirazóis/farmacologia , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 17(11): 2992-7, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17418570

RESUMO

DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.


Assuntos
Compostos de Benzil/química , Compostos de Benzil/farmacologia , Inibidores do Citocromo P-450 CYP2D6 , Compostos de Fenilureia/química , Piperidinas/química , Piperidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Compostos de Benzil/síntese química , Bioensaio , Células Cultivadas , Humanos , Camundongos , Pan troglodytes , Compostos de Fenilureia/farmacologia , Piperidinas/síntese química , Receptores CCR3 , Relação Estrutura-Atividade
11.
J Med Chem ; 50(6): 1365-79, 2007 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-17315987

RESUMO

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.


Assuntos
Fármacos Antiobesidade/síntese química , Indóis/síntese química , Pirazinas/síntese química , Agonistas do Receptor 5-HT2 de Serotonina , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Condicionamento Operante , Comportamento Alimentar/efeitos dos fármacos , Humanos , Indóis/química , Indóis/farmacologia , Isoindóis , Masculino , Camundongos , Necrose , Células Parietais Gástricas/efeitos dos fármacos , Células Parietais Gástricas/patologia , Pirazinas/química , Pirazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Ganho de Peso/efeitos dos fármacos
12.
J Med Chem ; 48(6): 2194-211, 2005 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-15771462

RESUMO

Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.


Assuntos
Cicloexanos/síntese química , Compostos de Fenilureia/síntese química , Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Disponibilidade Biológica , Células CHO , Células CACO-2 , Cálcio/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Cricetinae , Cicloexanos/química , Cicloexanos/farmacologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/fisiologia , Feminino , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Técnicas In Vitro , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Permeabilidade , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores CCR3 , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/síntese química , Ureia/química , Ureia/farmacologia
14.
Bioorg Med Chem Lett ; 14(7): 1645-9, 2004 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-15026042

RESUMO

The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s.


Assuntos
Piperidinas/metabolismo , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/metabolismo , Ureia/análogos & derivados , Ureia/metabolismo , Animais , Células CHO , Bovinos , Cricetinae , Piperidinas/química , Ligação Proteica/fisiologia , Receptores CCR3 , Ureia/química
15.
J Comb Chem ; 4(5): 536-9, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12217028

RESUMO

Alkyl aryl ether formation is a frequently employed reaction in organic synthesis. Ullmann condensation is an alternative method to the widely used Mitsunobu reaction and is very useful in situations where application of the Mitsunobu reaction is limited. By application of this reaction to solid-phase synthesis of a series of alkyl aryl ethers, reaction conditions (catalyst, solvent, temperature, time, etc.) for a sterically hindered class of alcohols were investigated and optimized. A range of aryl halides was used to explore the scope of the reaction in solid phase.

16.
Bioorg Med Chem Lett ; 12(13): 1785-9, 2002 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-12067561

RESUMO

CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.


Assuntos
Antiasmáticos/química , Antiasmáticos/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Alquilação , Amidas/química , Amidas/metabolismo , Cálcio/metabolismo , Quimiocina CCL11 , Quimiocinas CC/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Piperidinas/química , Receptores CCR3 , Receptores de Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA