RESUMO
Nodulisporic acid A (NSA) has been shown previously to be safe in dogs and to deliver >90% flea control for 4 days following a single oral administration. Three newly prepared nodulisporamide derivatives were subsequently identified from an artificial membrane flea feeding system as exhibiting potency substantially greater than NSA. To determine if they have superior in vivo activity, these 3 nodulisporamides, as well as NSA, were evaluated in dogs at 15 mg/kg/os. Parasite challenges were made by placing 100 live Ctenocephalides felis fleas onto the dorsum of dogs every 48 hr and examining efficacy at each of those intervals over a 22-day period. Results showed that NSA produced >90% efficacy at day 2 and 81% efficacy at day 4, and its residual flea killing fell to approximately 50% by day 6 posttreatment. All dogs treated with the 3 new experimental nodulisporamides were 100% protected from flea challenges to day 8 posttreatment, and 2 of the compounds continued to produce >90% residual activity to 2 wk posttreatment. Pharmacokinetic analysis showed that plasma profiles and half-lives of NSA and these 3 new compounds correlated closely with flea efficacy. These results demonstrate that specific substitutions to the pharmacophore of NSA can substantially increase the duration of activity against fleas.
Assuntos
Doenças do Cão/parasitologia , Indóis/farmacologia , Inseticidas/farmacologia , Sifonápteros , Administração Oral , Amidas/sangue , Amidas/farmacocinética , Amidas/farmacologia , Animais , Doenças do Cão/tratamento farmacológico , Doenças do Cão/metabolismo , Cães , Meia-Vida , Indóis/sangue , Indóis/farmacocinética , Inseticidas/sangue , Inseticidas/farmacocinética , Masculino , Distribuição AleatóriaRESUMO
[reaction--see text] The semisynthetic conversion of nodulisporic acid A (1) into a set of three heterocyclic side chain derivatives provided compounds, highlighted by 6, with an improved spectrum of ectoparasiticidal activity and pharmacokinetic profile relative to the natural product.
Assuntos
Indóis/síntese química , Inseticidas/síntese química , Oxazóis/síntese química , Tiazóis/síntese química , Animais , Sifonápteros , CarrapatosRESUMO
A series of 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing hormone receptor assay. Some para-substituents on the 4-phenylbutyl side chain attached to the tryptamine nitrogen led to compounds with potent GnRH receptor binding. The study has helped define structural requirements for GnRH receptor binding for the 2-aryltryptamine GnRH antagonists.
Assuntos
Antagonistas de Hormônios/metabolismo , Antagonistas de Hormônios/farmacologia , Receptores LHRH/metabolismo , Triptaminas/síntese química , Triptaminas/metabolismo , Triptaminas/farmacologia , Animais , Sítios de Ligação/fisiologia , Desenho de Fármacos , Feminino , Antagonistas de Hormônios/química , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Triptaminas/químicaRESUMO
A series of heterocyclic 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing hormone receptor assay. The carbon tether length and heterocyclic ring attached to the amino group of 2-(3,5-dimethylphenyl)tryptamine were varied. Several of these derivatives were potent GnRH antagonists with the most potent compound having an IC50 of 16 nM.
Assuntos
Compostos Heterocíclicos/síntese química , Antagonistas de Hormônios/metabolismo , Receptores LHRH/metabolismo , Triptaminas/síntese química , Triptaminas/metabolismo , Animais , Sítios de Ligação/fisiologia , Desenho de Fármacos , Feminino , Antagonistas de Hormônios/química , Concentração Inibidora 50 , RatosRESUMO
Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the 6-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 10(4)-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates.
Assuntos
Azetidinas/síntese química , Quinolonas/síntese química , Receptores LHRH/antagonistas & inibidores , Animais , Azetidinas/química , Azetidinas/farmacocinética , Azetidinas/farmacologia , Ligação Competitiva , Células CHO , Cricetinae , Humanos , Técnicas In Vitro , Macaca mulatta , Hipófise/metabolismo , Quinolonas/química , Quinolonas/farmacocinética , Quinolonas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
A nonpeptidyl GnRH receptor antagonist (1), with a unique 2-arylindole core, was identified through the Merck in-house screening for binding affinity on the rat GnRH receptor. SAR studies directed toward the alkoxy-ethanolamine and 2-aryl groups resulted in a simpler lead structure with improved activity. This compound 50 exhibits a 60-fold improvement in binding activity over our initial lead 1.
Assuntos
Indóis/farmacologia , Receptores LHRH/antagonistas & inibidores , Animais , Ratos , Relação Estrutura-AtividadeRESUMO
The discovery of the potency-enhancing effect of 5-substitutions on the novel 2-arylindoles as nonpeptidyl GnRH receptor antagonists led to the identification of several analogues with high affinities on the GnRH receptor. The syntheses and SARs of these 5-substituted-2-arylindole analogues are reported.
Assuntos
Indóis/farmacologia , Receptores LHRH/antagonistas & inibidores , Animais , Ratos , Relação Estrutura-AtividadeRESUMO
Apicidin, a natural product recently isolated at Merck, inhibits both mammalian and protozoan histone deacetylases (HDACs). The conversion of apicidin, a nanomolar inhibitor of HDACs, into a series of side-chain analogues that display picomolar enzyme affinity is described within this structure-activity study.
Assuntos
Antiprotozoários/síntese química , Inibidores de Histona Desacetilases , Peptídeos Cíclicos/farmacologia , Animais , Antiprotozoários/farmacologia , Fatores Biológicos/farmacologia , Bovinos , Linhagem Celular , Técnicas de Química Combinatória , Eimeria tenella/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fusarium/química , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/síntese química , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Recently isolated at Merck, apicidin inhibits both mammalian and protozoan histone deacetylases (HDACs). The conversion of apicidin, a nonselective nanomolar inhibitor of HDACs, into a series of picomolar indole-modified and parasite-selective tryptophan-replacement analogues is described within this structure-activity study.
Assuntos
Antiprotozoários/síntese química , Inibidores de Histona Desacetilases , Peptídeos Cíclicos/farmacologia , Animais , Antiprotozoários/farmacologia , Fatores Biológicos/farmacologia , Bovinos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Técnicas de Química Combinatória , Eimeria tenella/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fusarium/química , Células HeLa , Humanos , Indóis/química , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/síntese química , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Triptofano/químicaRESUMO
Pyridineethanolamine derivatives containing cyanoguanidine or nitroethylenediamine moieties were examined as human beta3 adrenergic receptor (AR) agonists. Notably, indoline derivatives 6a and 11 were potent beta3 AR agonists (beta3 EC50 = 13 and 19 nM, respectively), which showed good selectivity over binding to and minimal activation of the beta1 and beta2 ARs.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Adenilil Ciclases/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Animais , Células CHO , Membrana Celular/química , Técnicas de Química Combinatória , Cricetinae , Diaminas/química , Etano/análogos & derivados , Etano/química , Guanidinas/química , Humanos , Concentração Inibidora 50 , Nitroparafinas/química , Ensaio Radioligante , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-AtividadeRESUMO
Apicidin's indole was efficiently converted into a series of N-substituted quinolone derivatives by indole N-alkylation followed by a two-step, one-pot, ozonolysis/aldol condensation protocol. The new quinolones exhibited good parasite selectivity and potency both at the level of their molecular target, histone deacetylase, and in their whole cell antiproliferative activity in vitro.
Assuntos
Antiprotozoários/síntese química , Inibidores Enzimáticos/síntese química , Inibidores de Histona Desacetilases , Indóis/síntese química , Peptídeos Cíclicos/química , Quinolonas/síntese química , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Ligação Competitiva , Divisão Celular/efeitos dos fármacos , Extratos Celulares , Galinhas , Eimeria tenella/citologia , Eimeria tenella/efeitos dos fármacos , Eimeria tenella/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Células HeLa , Histona Desacetilases/metabolismo , Humanos , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Fígado/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/química , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
As part of our investigation into the development of orally bioavailable beta(3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta(3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F(3)C-C(6)H(4)) is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Sulfonamidas/síntese química , Tiazóis/síntese química , Administração Oral , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacologia , Animais , Disponibilidade Biológica , Células CHO , Clonagem Molecular , Cricetinae , Cães , Glicerol/sangue , Humanos , Macaca mulatta , Masculino , Ensaio Radioligante , Ratos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
Tetrahydroisoquinoline derivatives containing a 4-(hexylureido)benzenesulfonamide were examined as human beta3 adrenergic receptor (AR) agonists. Notably, 4,4-biphenyl derivative 9 was a 6 nM full agonist of the beta3 AR. Naphthyloxy compound 18 (beta3 EC50 = 78 nM) did not activate the beta1 and beta2 ARs at 10 microM, and showed >1000-fold selectivity over binding to the beta1 and beta2 ARs.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Amidas/síntese química , Isoquinolinas/síntese química , Peptídeos/síntese química , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Amidas/química , Desenho de Fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Modelos Moleculares , Conformação Molecular , Peptídeos/química , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Medicinal chemistry efforts were initiated to identify the key constituents of the nodulisporic acid A (1) pharmacophore that are integral to its potent insecticidal activity. New semisynthetic derivatives delineated 1 into 'permissive' and 'nonpermissive' regions and led to the discovery of new nodulisporamides with significantly improved flea efficacy.
Assuntos
Indóis/química , Indóis/síntese química , Inseticidas/síntese química , Animais , Desenho de Fármacos , Indóis/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Estrutura Molecular , Sifonápteros , Relação Estrutura-AtividadeRESUMO
A series of thiazole benzenesulfonamide-substituted 3-pyridylethanolamines was prepared and evaluated for their human beta3 adrenergic receptor agonist activity. Incorporation of aryl and heteroaryl substitution in the 4-position of the thiazole ring resulted in a number of highly potent and selective beta3 agonists. Results of preliminary in vivo evaluation of several of these compounds is described.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Etanolaminas/síntese química , Sulfonamidas/síntese química , Tiazóis/síntese química , Agonistas Adrenérgicos beta/farmacologia , Animais , Células CHO , Cricetinae , Humanos , Relação Estrutura-Atividade , BenzenossulfonamidasRESUMO
Compounds containing a 1,2,3-triazole-substituted benzenesulfonamide were prepared and found to be potent and selective human beta3-adrenergic receptor agonists. The most interesting compound, trifluoromethylbenzyl analogue 12e (beta3 EC50 = 3.1 nM with >1500-fold selectivity over binding to both beta1- and beta2 receptors), stimulates lipolysis in the rhesus monkey (ED50 = 0.36 mg/kg) and is 25% orally bioavailable in the dog.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Administração Oral , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Cães , Relação Dose-Resposta a Droga , Humanos , Infusões Parenterais , Isoproterenol/farmacologia , Lipólise/efeitos dos fármacos , Macaca mulatta , Ligação Proteica , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Taquicardia/induzido quimicamente , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética , BenzenossulfonamidasRESUMO
A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal.
Assuntos
Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Quinolonas/farmacologia , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
5-n-Pentyl oxadiazole substituted benzenesulfonamide 8 is a potent and selective beta3 adrenergic receptor agonist (beta3 EC50 = 23 nM, beta1 IC50 = 3000 nM, beta2 IC50 = 3000 nM). The compound has high oral bioavailability in dogs (62%) and rats (36%) and is among the most orally bioavailable beta3 adrenergic receptor agonists reported to date.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacologia , Agonistas Adrenérgicos beta/farmacocinética , Oxidiazóis/farmacologia , Oxidiazóis/farmacocinética , Administração Oral , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/química , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cães , Desenho de Fármacos , Humanos , Estrutura Molecular , Oxidiazóis/administração & dosagem , Oxidiazóis/química , Ratos , Relação Estrutura-AtividadeRESUMO
Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable beta3 adrenergic receptor (AR) agonists. The 4-trifluormethoxy substituted 5-benzyl oxadiazole 5f has an EC50 of 8 nM in the beta3 AR agonist assay with 100-fold selectivity over beta1 and beta2 AR binding inhibition activity. Its oral bioavailability in dogs is 30 +/- 4%, with a half-life of 3.8 +/- 0.4 h. In the anesthetized rhesus, 5f evoked a dose-dependent glycerolemia (ED50Gly = 0.15 mg/kg). Under these conditions a heart rate increase of 15% was observed at a dose level of 10 mg/kg.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacologia , Fármacos Antiobesidade/farmacologia , Oxidiazóis/farmacologia , Sulfonamidas/farmacologia , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/química , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Disponibilidade Biológica , Células CHO , Cricetinae , Cães , Desenho de Fármacos , Glicerol/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Macaca mulatta , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
As a part of our investigation into the development of orally bioavailable beta3 adrenergic receptor agonists, we have identified a series of substituted oxazole derivatives that are potent beta3 agonists with excellent selectivity against other beta receptors. Several of these compounds showed excellent oral bioavailability in dogs. One example, cyclopentylethyloxazole 5f is a potent beta3 agonist (EC50 = 14 nM, 84% activation) with 340-fold and 160-fold selectivity over beta1 and beta2 receptors, respectively, and has 38% oral bioavailability in dogs.