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1.
Chimia (Aarau) ; 71(10): 722-729, 2017 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-29070417

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 , Ratos
2.
PLoS Med ; 13(10): e1002138, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27701420

RESUMO

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.


Assuntos
Acrilamidas/farmacologia , Antimaláricos/farmacologia , Piperazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Acrilamidas/farmacocinética , Animais , Antimaláricos/farmacocinética , Artemisininas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Piperazinas/farmacocinética , Plasmodium berghei/efeitos dos fármacos
3.
Bioorg Med Chem Lett ; 25(9): 1884-91, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25838147

RESUMO

Starting from advanced pyrrolidin-2-one lead compounds, this novel series of small-molecule orexin receptor antagonists was further optimized by fine-tuning of the C-3 substitution at the γ-lactam ring. We discuss our design to align in vitro potency with metabolic stability and improved physicochemical/pharmacokinetic properties while avoiding P-glycoprotein-mediated efflux. These investigations led to the identification of the orally active 3-hydroxypyrrolidin-2-one 46, a potent and selective orexin-2 receptor antagonist, that achieved good brain exposure and promoted physiological sleep in rats.


Assuntos
Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Pirrolidinonas/farmacologia , Sono/efeitos dos fármacos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Humanos , Lactamas/administração & dosagem , Lactamas/farmacologia , Estrutura Molecular , Antagonistas dos Receptores de Orexina/síntese química , Antagonistas dos Receptores de Orexina/química , Pirrolidinonas/síntese química , Pirrolidinonas/química , Ratos , Relação Estrutura-Atividade
4.
J Biol Chem ; 288(31): 22576-83, 2013 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-23754276

RESUMO

A representative of a new class of potent antimalarials with an unknown mode of action was recently described. To identify the molecular target of this class of antimalarials, we employed a photo-reactive affinity capture method to find parasite proteins specifically interacting with the capture compound in living parasitized cells. The capture reagent retained the antimalarial properties of the parent molecule (ACT-213615) and accumulated within parasites. We identified several proteins interacting with the capture compound and established a functional interaction between ACT-213615 and PfMDR1. We surmise that PfMDR1 may play a role in the antimalarial activity of the piperazine-containing compound ACT-213615.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Antimaláricos/farmacologia , Plasmodium falciparum/fisiologia , Raios Ultravioleta , Animais
5.
Bioorg Med Chem Lett ; 24(4): 1201-8, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24447850

RESUMO

Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization.


Assuntos
Descoberta de Drogas , Lactamas/farmacologia , Antagonistas dos Receptores de Orexina , Animais , Relação Dose-Resposta a Droga , Humanos , Lactamas/química , Lactamas/metabolismo , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade
6.
J Infect Dis ; 206(5): 735-43, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22732921

RESUMO

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC(50)) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential.


Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Parasitemia/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium berghei/efeitos dos fármacos , Animais , Antimaláricos/farmacocinética , Disponibilidade Biológica , Linhagem Celular , Eritrócitos/parasitologia , Concentração Inibidora 50 , Malária/sangue , Malária/parasitologia , Camundongos , Parasitemia/parasitologia , Piperazinas/farmacocinética , Ratos
7.
ChemMedChem ; 15(23): 2286-2305, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-32937014

RESUMO

Since its discovery in 1998, the orexin system has been of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders, stress and anxiety disorders, addiction or eating disorders. It consists of two G protein-coupled receptors, the orexin 1 and orexin 2 receptors, and two neuropeptides with agonistic effects, the orexin A and orexin B peptides. Herein we describe our efforts leading to the identification of a promising set of dual orexin receptor antagonists (DORAs) which subsequently went through physiology-based pharmacokinetic and pharmacodynamic modelling>[1] and finally led to the selection of daridorexant, currently in phase 3 clinical trials for the treatment of insomnia disorders.


Assuntos
Imidazóis/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Pirrolidinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Imidazóis/química , Estrutura Molecular , Antagonistas dos Receptores de Orexina/química , Pirrolidinas/química , Distúrbios do Início e da Manutenção do Sono/metabolismo
8.
ChemMedChem ; 15(5): 430-448, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31945272

RESUMO

The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone (6), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone (42), a DORA with improved in vivo efficacy compared to 6.


Assuntos
Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Oxidiazóis/farmacologia , Triazóis/farmacologia , Animais , Cães , Masculino , Conformação Molecular , Antagonistas dos Receptores de Orexina/química , Oxidiazóis/química , Ratos , Ratos Wistar , Sono/efeitos dos fármacos , Estereoisomerismo , Triazóis/química
9.
ChemMedChem ; 14(13): 1257-1270, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31066976

RESUMO

The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone (3), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone (51), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.


Assuntos
Antagonistas dos Receptores de Orexina/síntese química , Receptores de Orexina/metabolismo , Oxidiazóis/química , Animais , Azepinas/farmacologia , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Cães , Meia-Vida , Humanos , Concentração Inibidora 50 , Antagonistas dos Receptores de Orexina/metabolismo , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/química , Oxidiazóis/metabolismo , Oxidiazóis/farmacologia , Ratos , Sono/efeitos dos fármacos , Relação Estrutura-Atividade , Triazóis/farmacologia
10.
J Med Chem ; 60(23): 9769-9789, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29116786

RESUMO

We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.


Assuntos
Benzenoacetamidas/química , Benzenoacetamidas/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Epilepsia Generalizada/tratamento farmacológico , Animais , Benzenoacetamidas/metabolismo , Benzenoacetamidas/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacocinética , Cães , Descoberta de Drogas , Epilepsia Generalizada/metabolismo , Cobaias , Humanos , Macaca fascicularis , Pirazóis/química , Pirazóis/farmacologia , Ratos Wistar , Relação Estrutura-Atividade
11.
ChemMedChem ; 11(19): 2132-2146, 2016 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-27390287

RESUMO

Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold-hopping approach. Structure-activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux. Compound 80 c [{(1S,6R)-3-(6,7-difluoroquinoxalin-2-yl)-3,8-diazabicyclo[4.2.0]octan-8-yl}(4-methyl-[1,1'-biphenyl]-2-yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium-release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep-promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Descoberta de Drogas , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Animais , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/química , Cães , Relação Dose-Resposta a Droga , Humanos , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Antagonistas dos Receptores de Orexina/síntese química , Antagonistas dos Receptores de Orexina/química , Ratos , Ratos Wistar , Sono/efeitos dos fármacos , Relação Estrutura-Atividade
12.
ChemMedChem ; 11(18): 1995-2014, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27471138

RESUMO

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 in 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-Atividade
13.
ChemMedChem ; 9(11): 2486-96, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25147058

RESUMO

The orexin system consists of two G-protein-coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.


Assuntos
Encéfalo/metabolismo , Neurotransmissores/química , Antagonistas dos Receptores de Orexina , Pirrolidinas/química , Sulfonamidas/química , Animais , Barreira Hematoencefálica/metabolismo , Cães , Meia-Vida , Humanos , Células Madin Darby de Rim Canino , Masculino , Neurotransmissores/farmacocinética , Receptores de Orexina/metabolismo , Prolina/química , Pirrolidinas/farmacocinética , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética
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