RESUMO
Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.
Assuntos
Analgésicos/química , Benzimidazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Carragenina , Cães , Adjuvante de Freund , Células HEK293 , Haplorrinos , Temperatura Alta , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay. Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced 'wet-dog' shaking in which compound 12 was fully effective. TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature.
Assuntos
Glicina/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glicina/análogos & derivados , Glicina/química , Células HEK293 , Humanos , Estrutura Molecular , Pirimidinonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Canais de Cátion TRPM/agonistasRESUMO
A series of benzothiophene-based phosphonates was synthesized and many analogs within the series were shown to be potent antagonists of the TRPM8 channel. The compounds were obtained as a racemic mixture in 5 synthetic steps, and were tested for TRPM8 antagonist activity in a recombinant, canine TRPM8-expressing cell line using a fluorometric imaging plate reader (FLIPR) assay. Structure-activity relationships were developed initially by modification of the core structure and subsequently by variation of the aromatic substituents and the phosphonate ester. Compound 9l was administered intraperitoneally to rats and demonstrated engagement of the TRPM8 target in both prevention and reversal-modes in an icilin-induced 'wet-dog' shake model.
Assuntos
Desenho de Fármacos , Organofosfonatos/síntese química , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cães , Concentração Inibidora 50 , Estrutura Molecular , Organofosfonatos/química , Organofosfonatos/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic ß-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic ß-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.
Assuntos
Ciproeptadina/toxicidade , Hiperglicemia/induzido quimicamente , Células Secretoras de Insulina/efeitos dos fármacos , Antagonistas de Entorpecentes/toxicidade , Pâncreas/efeitos dos fármacos , Antagonistas da Serotonina/toxicidade , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciproeptadina/análogos & derivados , Diabetes Mellitus Tipo 1/metabolismo , Cães , Epífises/anormalidades , Epífises/metabolismo , Feminino , Ensaios de Triagem em Larga Escala , Hiperglicemia/metabolismo , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Insulinoma/tratamento farmacológico , Insulinoma/metabolismo , Masculino , Camundongos , Osteocondrodisplasias/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Ratos , Ratos Sprague-Dawley , Vacúolos/efeitos dos fármacos , Vacúolos/ultraestruturaRESUMO
Mu-opioid analgesics are a mainstay in the treatment of acute and chronic pain of multiple origins, but their side effects, such as constipation, respiratory depression, and abuse liability, adversely affect patients. The recent demonstration of the up-regulation and membrane targeting of the delta-opioid receptor (DOR) following inflammation and the consequent enhanced therapeutic effect of delta-opioid agonists have enlivened the search for delta-opioid analgesic agents. JNJ-20788560 [9-(8-azabicyclo-[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide] had an affinity of 2.0 nM for DOR (rat brain cortex binding assay) and a naltrindole sensitive DOR potency of 5.6 nM (5'-O-(3-[(35)S]thio)triphosphate assay). The compound had a potency of 7.6 mg/kg p.o. in a rat zymosan radiant heat test and of 13.5 mg/kg p.o. in a rat Complete Freund's adjuvant RH test but was virtually inactive in an uninflamed radiant heat test. In limited studies, tolerance was not observed to the antihyperalgesic or antinociceptive effects of the compound. Unlike ibuprofen, JNJ-20788560 did not produce gastrointestinal (GI) erosion. Although morphine reduced GI motility at all doses tested and reached nearly full effect at the highest dose, JNJ-20788560 did not retard transit at the lowest dose and reached only 11% reduction at the highest dose administered. Unlike morphine, JNJ-20788560 did not exhibit respiratory depression (blood gas analysis), and no withdrawal signs were precipitated by the administration of opioid (mu or delta) antagonists. Coupled with the previously published lack of self-administration behavior of the compound by alfentanil-trained primates, these findings strongly recommend delta-opioid agonists such as JNJ-20788560 for the relief of inflammatory hyperalgesia.
Assuntos
Analgésicos Opioides , Compostos Azabicíclicos/farmacologia , Hiperalgesia/tratamento farmacológico , Receptores Opioides delta/agonistas , Insuficiência Respiratória/induzido quimicamente , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Xantenos/farmacologia , Alfentanil/farmacologia , Animais , Compostos Azabicíclicos/efeitos adversos , Compostos Azabicíclicos/toxicidade , Cricetinae , Tolerância a Medicamentos , Motilidade Gastrointestinal/efeitos dos fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Temperatura Alta , Irritantes/toxicidade , Masculino , Camundongos , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Opioides delta/metabolismo , Insuficiência Respiratória/fisiopatologia , Convulsões/induzido quimicamente , Autoadministração , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Síndrome de Abstinência a Substâncias/psicologia , Xantenos/efeitos adversos , Xantenos/toxicidade , ZimosanRESUMO
High throughput screening of our compound library revealed a series of N-pyridyl-3-benzamides as low micromolar agonists of the human TRPV1 receptor. Synthesis of analogs in this series led to the discovery of a series of N-quinolin-3-yl-benzamides as low nanomolar antagonists of human TRPV1.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Isoquinolinas/química , Piridinas/química , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Animais , Benzamidas/química , Benzamidas/uso terapêutico , Reagentes de Ligações Cruzadas/química , Humanos , Hiperalgesia/tratamento farmacológico , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.
Assuntos
Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Tetra-Hidronaftalenos/farmacologia , Ureia/farmacologia , Ligação Competitiva/efeitos dos fármacos , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Canais de Cátion TRPV/química , Tetra-Hidronaftalenos/química , Ureia/análogos & derivados , Ureia/químicaRESUMO
High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.
Assuntos
Aminopiridinas/síntese química , Analgésicos/síntese química , Canais Iônicos/antagonistas & inibidores , Piperazinas/síntese química , Administração Oral , Aminopiridinas/química , Aminopiridinas/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Temperatura Corporal/efeitos dos fármacos , Cálcio/metabolismo , Capsaicina , Linhagem Celular , Humanos , Hipotermia/induzido quimicamente , Hipotermia/prevenção & controle , Canais Iônicos/agonistas , Masculino , Medição da Dor , Piperazinas/química , Piperazinas/farmacologia , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPVRESUMO
Two parallel synthetic methods were developed to explore the structure-activity relationships (SAR) of a series of potent opioid agonists. This series of tropanylidene benzamides proved extremely tolerant of structural variation while maintaining excellent opioid activity. Evaluation of several representative compounds from this series in the mouse hot plate test revealed potent antinociceptive effects upon oral administration.
Assuntos
Analgésicos , Benzamidas , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos/síntese química , Analgésicos/química , Animais , Benzamidas/síntese química , Benzamidas/química , Camundongos , Estrutura Molecular , Medição da Dor/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Starting from a low micromolar agonist lead identified by high-throughput screening, series of N-isoquinolin-5-yl-N'-aralkyl ureas and analogous amides were developed as potent antagonists of human vanilloid receptor 1 (VR1). The synthesis and structure-activity relationships (SAR) of the series are described.
Assuntos
Amidas/química , Isoquinolinas/química , Receptores de Droga/antagonistas & inibidores , Ureia/química , Amidas/metabolismo , Linhagem Celular , Humanos , Isoquinolinas/metabolismo , Receptores de Droga/metabolismo , Canais de Cátion TRPV , Ureia/metabolismoRESUMO
A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the delta opioid receptor with excellent selectivity versus the micro opioid receptor. They were full agonists at the delta opioid receptor, as assessed by stimulation of GTPgammaS binding, and displayed antinociceptive activity.
Assuntos
Analgésicos Opioides/farmacologia , Benzamidas/farmacologia , Receptores Opioides delta/agonistas , Analgésicos Opioides/química , Benzamidas/química , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Relação Estrutura-AtividadeRESUMO
The tertiary amide delta opioid agonist 2 is a potent antinociceptive agent. Compound 2 was metabolized in vitro and in vivo to secondary amide 3, a potent and selective micro opioid agonist. The SAR of a series of N-alkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides was examined.
Assuntos
Analgésicos/farmacologia , Benzamidas/farmacologia , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos/química , Benzamidas/química , Relação Estrutura-AtividadeRESUMO
Through SAR studies of a piperidinylindoline cinnamide HTS lead, the first potent, non-peptide, low molecular weight selective Neuropeptide Y Y2 (NPY Y2) antagonists have been synthesized. The SAR studies around the piperidinyl, the indolinyl, and the cinnamyl moieties are discussed.
Assuntos
Piperidinas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Humanos , Piperidinas/metabolismo , Piperidinas/farmacologia , Ligação Proteica , Receptores de Neuropeptídeo Y/metabolismoRESUMO
A series of structurally simple 7-hydroxynaphthalenyl ureas and amides were discovered to be potent ligands of human vanilloid receptor 1 (VR1). 1-(7-Hydroxynaphthalen-1-yl)-3-(4-trifluoromethylbenzyl)urea 5f exhibited nanomolar binding affinity (K(i)=1.0nM) and upon capsaicin challenge, behaved as a potent functional antagonist (IC(50)=4nM). The synthesis and structure-activity relationships (SARs) for the series are described.
Assuntos
Amidas/química , Naftóis/química , Receptores de Droga/antagonistas & inibidores , Receptores de Droga/metabolismo , Ureia/química , Amidas/metabolismo , Humanos , Naftóis/metabolismo , Ligação Proteica/fisiologia , Canais de Cátion TRPV , Ureia/metabolismoRESUMO
The design and synthesis of novel pyrrolidine-containing bradykinin antagonists, II, are described. Conformational analysis suggested that a pyrrolidine moiety could substitute for the N-methyl cis-amide moiety of FR 173657. The in vitro binding data showed that the (S)-isomer of II was potent in the bradykinin B(2) receptor-binding assay with a K(i) of 33 nM. The opposite isomer, (R)-II, had a K(i) of 46 nM. The in vitro binding data confirmed our conformational hypothesis.
Assuntos
Bradicinina/antagonistas & inibidores , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Desenho de Fármacos , Isomerismo , Modelos Moleculares , Conformação Molecular , Receptores da Bradicinina/metabolismoRESUMO
The synthesis and structure-activity relationships of a novel series of aroylpyrrole alkylamides as potent selective bradykinin B(2) receptor antagonists are described. Several members of this series display nanomolar affinity at the B(2) receptor and show activity in an animal model of antinociception.
Assuntos
Alcanos/síntese química , Alcanos/farmacologia , Antagonistas dos Receptores da Bradicinina , Pirróis/síntese química , Pirróis/farmacologia , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Indicadores e Reagentes , Irritantes/antagonistas & inibidores , Caulim , Camundongos , Medição da Dor/efeitos dos fármacos , Receptor B2 da Bradicinina , Relação Estrutura-AtividadeRESUMO
Using a 'directed' iodination procedure, novel iodo-resiniferatoxin congeners were synthesized from 4-acetoxy-3-methoxyphenylacetic acid and resiniferinol- 9,13,14-ortho-phenylacetate (ROPA). The 2-iodo-4-hydroxy-5-methoxyphenylacetic acid ester of resiniferinol 5 displayed high affinity binding (K(i)=0.71 nM) for the human vanilloid VR1 receptor and functioned as a partial agonist.