RESUMO
Heart failure (HF) treatment remains a critical unmet medical need. Studies in normal healthy volunteers and HF patients have shown that [Pyr1]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac function. However, the short half-life of [Pyr1]apelin-13 and the need for intravenous administration have limited the therapeutic potential for chronic use. We sought to identify potent, small-molecule APJ agonists with improved pharmaceutical properties to enable oral dosing in clinical studies. In this manuscript, we describe the identification of a series of pyrimidinone sulfones as a structurally differentiated series to the clinical lead (compound 1). Optimization of the sulfone series for potency, metabolic stability and oral bioavailability led to the identification of compound 22, which showed comparable APJ potency to [Pyr1]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.
Assuntos
Receptores de Apelina/agonistas , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/farmacocinética , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Animais , Área Sob a Curva , Fármacos Cardiovasculares/síntese química , Desenho de Fármacos , Meia-Vida , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Macaca fascicularis , Estrutura Molecular , Pirimidinonas/química , Pirimidinonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (Ctroughâ¯>â¯15 fold over mouse plasma EL IC50 over 4â¯days).
RESUMO
Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection.
Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Antagonistas dos Receptores de Neurocinina-1/química , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Antidepressivos/química , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Compostos de Bifenilo/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Gerbillinae , Humanos , Antagonistas dos Receptores de Neurocinina-1/farmacocinética , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinéticaRESUMO
Several new potent CGRP receptor antagonists have been prepared in which the amide bond of lead compound 1 has been replaced by bioisosteric imidazole moieties. Substitution at N-1 of the imidazole was optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of the imidazole to form tetrahydroimidazo[1,5-a]pyrazine 43 gave substantially improved permeability.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Imidazóis/química , Quinolonas/química , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Microssomos/metabolismo , Ligação Proteica , Quinolonas/síntese química , Quinolonas/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Relação Estrutura-AtividadeRESUMO
Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%).
Assuntos
Aminoácidos/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indazóis/síntese química , Quinazolinonas/síntese química , Tirosina/química , Administração Intranasal , Aminoácidos/síntese química , Aminoácidos/farmacocinética , Animais , Benzoxazóis/química , Disponibilidade Biológica , Meia-Vida , Indazóis/química , Indazóis/farmacocinética , Ligação Proteica , Quinazolinonas/química , Quinazolinonas/farmacocinética , Coelhos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.
Assuntos
Depressão/tratamento farmacológico , Desenho de Fármacos , Antagonistas dos Receptores de Neurocinina-1 , Piridinas/síntese química , Antagonistas da Serotonina , Animais , Modelos Animais de Doenças , Gerbillinae , Concentração Inibidora 50 , Estrutura Molecular , Piridinas/química , Piridinas/uso terapêutico , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/uso terapêuticoRESUMO
Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.
Assuntos
HDL-Colesterol/metabolismo , Inibidores Enzimáticos/farmacologia , Cetonas/farmacologia , Lipase/antagonistas & inibidores , Oxidiazóis/farmacologia , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Cetonas/síntese química , Cetonas/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Relação Estrutura-AtividadeRESUMO
Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL. Optimization for selectivity versus hepatic lipase and pharmacokinetic properties resulted in the discovery of 24, which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure.
RESUMO
Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.