RESUMO
We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/efeitos dos fármacos , Descoberta de Drogas , Epilepsia Generalizada/tratamento farmacológico , Animais , Canais de Cálcio Tipo T/fisiologia , Modelos Animais de Doenças , Humanos , Camundongos , RatosRESUMO
The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Renina/antagonistas & inibidores , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Desenho de Fármacos , Modelos Moleculares , Piperidinas/química , Conformação Proteica , Ratos , Relação Estrutura-Atividade , Difração de Raios XRESUMO
The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK-1597), a renin inhibitor with a suitable profile for development is described.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Renina/antagonistas & inibidores , Angiotensinogênio/genética , Animais , Animais Geneticamente Modificados , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/química , Humanos , Indicadores e Reagentes , Modelos Moleculares , Piperidinas/química , Ratos , Renina/genética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
New classes of de novo designed renin inhibitors are reported. Some of these compounds display excellent in vitro and in vivo activities toward human renin in a TGR model. The synthesis of these new types of mono- and bicyclic scaffolds are reported, and properties of selected compounds discussed.
Assuntos
Compostos Bicíclicos com Pontes/classificação , Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Renina/antagonistas & inibidores , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.
Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Epilepsia/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Animais , Anticonvulsivantes/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Bloqueadores dos Canais de Cálcio/farmacocinética , Canais de Cálcio Tipo T/metabolismo , Modelos Animais de Doenças , Cães , Eletroencefalografia , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Humanos , Excitação Neurológica/efeitos dos fármacos , Masculino , Pirazóis/farmacocinética , Ratos WistarRESUMO
More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and inâ vivo pharmacological efficacy.
Assuntos
Acrilamidas/farmacologia , Antimaláricos/farmacologia , Descoberta de Drogas , Malária/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Acrilamidas/síntese química , Acrilamidas/química , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-AtividadeRESUMO
Since its discovery in 1988 by Yanagisawa et al., endothelin (ET), a potent vasoconstrictor, has been widely implicated in the pathophysiology of cardiovascular, cerebrovascular, and renal diseases. Many research groups have embarked on the discovery and development of ET receptor antagonists for the treatment of such diseases. While several compounds, e.g., ambrisentan 2, are in late clinical trials for various indications, one compound (bosentan, Tracleer) is being marketed to treat pulmonary arterial hypertension. Inspired by the structure of ambrisentan 2, we designed a novel class of ET receptor antagonists based on a 1,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-one scaffold. Here, we report on the preparation as well as the in vitro and in vivo structure-activity relationships of these derivatives. Potent dual ET(A)/ET(B) receptor antagonists with affinities in the low nanomolar range have been identified. In addition, several compounds efficiently reduced arterial blood pressure after oral administration to Dahl salt sensitive rats. In this animal model, the efficacy of the benzo[e][1,4]diazepin-2-one derivative rac-39au was superior to that of racemic ambrisentan, rac-2.
Assuntos
Benzodiazepinas/síntese química , Antagonistas do Receptor de Endotelina A , Antagonistas do Receptor de Endotelina B , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Inibidores das Enzimas do Citocromo P-450 , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ratos , Ratos Endogâmicos Dahl , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
Assuntos
Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Renina/antagonistas & inibidores , Sítios de Ligação , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
In order to overcome the problem of drug resistance in malaria, it appears wise to concentrate drug discovery efforts toward new structural classes and new mechanisms of action. We report our results, targeting Plasmepsin II, a Plasmodium falciparum aspartic protease active in hemoglobin degradation, a parasite specific catabolic pathway. The results show that the new structural class is not only inhibiting PMII in vitro but is also active in a P. falciparum infected human red blood cell assay.
Assuntos
Antimaláricos/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos , Inibidores Enzimáticos/farmacologia , Proteínas de Protozoários , Relação Estrutura-AtividadeRESUMO
Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas disease, a major cause of cardiovascular disease in many Latin American countries. There is an urgent need to develop an improved therapy due to the toxicity of existing drugs and emerging drug resistance. Cruzain, the primary cysteine protease of T. cruzi, is essential for the survival of the parasite in host cells and therefore is an important target for the development of inhibitors as potential therapeutics. A novel series of alpha-ketoamide-, alpha-ketoacid-, alpha-ketoester-, and aldehyde-based inhibitors of cruzain has been developed. The inhibitors were identified by screening protease targeted small molecule libraries and systematically optimizing the P1, P2, P3, and P1' residues using specific structure-guided methods. A total of 20 compounds displayed picomolar potency in in vitro assays and three inhibitors representing different alpha-keto-based inhibitor scaffolds demonstrated anti-trypanosomal activity in cell culture. A 2.3A crystallographic structure of cruzain bound with one of the alpha-ketoester analogs is also reported. The structure and kinetic assay data illustrate the covalent binding, reversible inhibition mechanism of the inhibitor. Information on the compounds reported here will be useful in the development of new lead compounds as potential therapeutic agents for the treatment of Chagas disease and as biological probes to study the role that cruzain plays in the pathology. This study also demonstrates the validity of structure-guided approaches to focused library design and lead compound optimization.