RESUMO
The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.
Assuntos
Amidas/farmacologia , Antimaláricos/farmacologia , Benzimidazóis/farmacologia , Eritrócitos/parasitologia , Malária/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Pirazóis/farmacologia , Sódio/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Humanos , Masculino , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/genética , Plasmodium berghei/metabolismo , Plasmodium falciparum/enzimologia , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas de ProtozoáriosRESUMO
We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.
RESUMO
The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
Assuntos
Anemia/tratamento farmacológico , Compostos Aza/síntese química , Hidantoínas/síntese química , Fator 1 Induzível por Hipóxia/metabolismo , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , Compostos de Espiro/síntese química , Animais , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Cães , Canal de Potássio ERG1 , Eritropoetina/biossíntese , Canais de Potássio Éter-A-Go-Go/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Hidantoínas/farmacocinética , Hidantoínas/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia , Indóis/síntese química , Indóis/farmacocinética , Indóis/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Macaca mulatta , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Regulação para CimaRESUMO
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Assuntos
Piperazinas/química , Receptor Tipo 4 de Melanocortina/agonistas , Ureia/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Haplorrinos , Camundongos , Obesidade/tratamento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.
RESUMO
We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.
RESUMO
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Assuntos
Obesidade/tratamento farmacológico , Receptor Tipo 4 de Melanocortina/agonistas , Triazóis/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Estrutura Molecular , Ratos , Receptor Tipo 4 de Melanocortina/genética , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêuticoRESUMO
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Assuntos
Ligantes , Receptor Tipo 4 de Melanocortina/agonistas , Animais , Humanos , Piperazina , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/metabolismo , Relação Estrutura-AtividadeRESUMO
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Assuntos
Amidas/química , Fármacos Antiobesidade/química , Obesidade/tratamento farmacológico , Pirrolidinas/química , Receptor Tipo 4 de Melanocortina/agonistas , Compostos de Espiro/química , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Peso Corporal/efeitos dos fármacos , Humanos , Camundongos , Camundongos Knockout , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/metabolismo , Compostos de Espiro/farmacocinética , Compostos de Espiro/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Assuntos
Piperidinas/química , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Animais , Encéfalo/metabolismo , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Conformação Molecular , Piperidinas/síntese química , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/metabolismo , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Assuntos
Disfunção Erétil/tratamento farmacológico , Indanos/química , Indanos/uso terapêutico , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/metabolismo , Compostos de Espiro/química , Compostos de Espiro/uso terapêutico , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Haplorrinos , Humanos , Indanos/farmacocinética , Indanos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Ligação Proteica , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50)=18 nM, hBRS-3) and functional agonist activity (EC(50)=47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.
Assuntos
Imidazóis/química , Imidazóis/uso terapêutico , Obesidade/tratamento farmacológico , Receptores da Bombesina/agonistas , Receptores da Bombesina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Imidazóis/farmacocinética , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.
Assuntos
Descoberta de Drogas , Imidazóis/química , Imidazóis/farmacologia , Receptores da Bombesina/agonistas , Animais , Disponibilidade Biológica , Humanos , Imidazóis/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.
Assuntos
Controle de Insetos , Inseticidas , Sifonápteros , Carrapatos , Tecido Adiposo/metabolismo , Administração Oral , Animais , Gatos , Cães , Feminino , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/farmacocinética , Alcaloides Indólicos/farmacologia , Indóis , Inseticidas/administração & dosagem , Inseticidas/síntese química , Masculino , Camundongos , Distribuição TecidualRESUMO
Novel 2,3-diarylindoles bearing an amine substituent at the indole 5- and 6-positions have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 27.
Assuntos
Coccidiostáticos/síntese química , Indóis/síntese química , Animais , Coccidiose/tratamento farmacológico , Coccidiose/enzimologia , Coccidiose/parasitologia , Coccidiostáticos/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria tenella/efeitos dos fármacos , Eimeria tenella/enzimologia , Eimeria tenella/crescimento & desenvolvimento , Indóis/farmacologia , Aves Domésticas/parasitologia , Piridinas/síntese químicaRESUMO
Novel 5,6-diarylimidazo[2,1-b][1,3]thiazoles bearing an amine substituent at the imidazothiazole 2-position have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 10.
Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Coccidiostáticos/química , Técnicas de Química Combinatória , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria/efeitos dos fármacos , Imidazóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/químicaRESUMO
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.
Assuntos
Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , TelomeraseRESUMO
Diaryl-(4-piperidinyl)-pyrrole derivatives bearing cyclic amine substituents have been synthesized and evaluated as anticoccidial agents. Improvements in potency of Et-PKG inhibition, such as azetidine derivative 3a, and broad spectrum anticoccidial activities in feed, such as morpholine derivative 8c, have been achieved.