RESUMO
Relaxin H2 is a clinically relevant peptide agonist for relaxin family peptide receptor 1 (RXFP1), but a combination of this hormone's short plasma half-life and the need for injectable delivery limits its therapeutic potential. We sought to overcome these limitations through the development of a potent small molecule (SM) RXFP1 agonist. Although two large SM HTS campaigns failed in identifying suitable hit series, we uncovered novel chemical space starting from the only known SM RXFP1 agonist series, represented by ML290. Following a design-make-test-analyze strategy based on improving early dose to man ranking, we discovered compound 42 (AZ7976), a highly selective RXFP1 agonist with sub-nanomolar potency. We used AZ7976, its 10 000-fold less potent enantiomer 43 and recombinant relaxin H2 to evaluate in vivo pharmacology and demonstrate that AZ7976-mediated heart rate increase in rats was a result of RXFP1 agonism. As a result, AZ7976 was selected as lead for continued optimization.
Assuntos
Relaxina , Humanos , Masculino , Ratos , Animais , Relaxina/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores de Peptídeos/agonistasRESUMO
Optimization of the highly potent and selective, yet metabolically unstable and poorly soluble hRXFP1 agonist AZ7976 led to the identification of the clinical candidate, AZD5462. Assessment of RXFP1-dependent cell signaling demonstrated that AZD5462 activates a highly similar panel of downstream pathways as relaxin H2 but does not modulate relaxin H2-mediated cAMP second messenger responsiveness. The therapeutic potential of AZD5462 was assessed in a translatable cynomolgus monkey heart failure model. Following 8 weeks of treatment with AZD5462, robust improvements in functional cardiac parameters including LVEF were observed at weeks 9, 13, and 17 without changes in heart rate or mean arterial blood pressure. AZD5462 was well tolerated in both rat and cynomolgus monkey and has successfully completed phase I studies in healthy volunteers. In summary, AZD5462 is a small molecule pharmacological mimetic of relaxin H2 signaling at RXFP1 and holds promise as a potential therapeutic approach to treat heart failure patients.
Assuntos
Insuficiência Cardíaca , Relaxina , Humanos , Ratos , Animais , Relaxina/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Macaca fascicularis/metabolismo , Receptores de Peptídeos/metabolismo , Insuficiência Cardíaca/tratamento farmacológicoRESUMO
Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia. To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6. Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2.
RESUMO
The synthesis and structure-activity relationship (SAR) of thiophene-C-glucosides have been explored, and the human sodium-dependent glucose cotransporter 2 (hSGLT2) inhibitory activities and rat urinary glucose excretion (UGE) effects of 3a-f were evaluated. As a result, they showed good hSGLT2 inhibitory activities and rat UGE effects. In particular, the chlorothiophene derivative 3f showed remarkable inhibitory activity against hSGLT2.
Assuntos
Glucose/metabolismo , Glucosídeos/química , Hipoglicemiantes/síntese química , Inibidores do Transportador 2 de Sódio-Glicose , Sorbitol/análogos & derivados , Tiofenos/química , Animais , Peso Corporal/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Glucosídeos/síntese química , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio/metabolismo , Sorbitol/síntese química , Sorbitol/química , Sorbitol/farmacologia , Relação Estrutura-AtividadeRESUMO
Inhibition of renal sodium-dependent glucose cotransporter 2 (SGLT2) increases urinary glucose excretion (UGE), and thus reduces blood glucose levels in hyperglycemia. A series of N-glucosides was synthesized for biological evaluation as human SGLT2 (hSGLT2) inhibitors. Among these compounds, N-glucoside 9d possessing an indole core structure showed good in vitro activity (IC50=7.1 nM against hSGLT2). Furthermore, 9d exhibited favorable in vivo potency with regard to UGE in rats based on good pharmacokinetic profiles.
Assuntos
Glucosídeos/química , Indóis/química , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Glucose/metabolismo , Glucosídeos/síntese química , Glucosídeos/farmacocinética , Meia-Vida , Humanos , Indóis/síntese química , Indóis/farmacocinética , Ligação Proteica , Ratos , Transportador 2 de Glucose-Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
Canagliflozin (1), a novel inhibitor for sodium-dependent glucose cotransporter 2 (SGLT2), has been developed for the treatment of type 2 diabetes. To investigate the effect of replacement of the phenyl ring in 1 with heteroaromatics, C-glucosides 2 were designed, synthesized, and evaluated for their inhibitory activities against SGLT2. Of these, 3-pyridyl, 2-pyrimidyl or 5-membered heteroaryl substituted derivatives showed highly potent inhibitory activity against SGLT2, while 5-pyrimidyl substitution was associated with slightly reduced activity. In particular, 2g (TA-3404) had remarkable anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
Assuntos
Glucosídeos/química , Hipoglicemiantes/química , Monossacarídeos/química , Piridinas/química , Inibidores do Transportador 2 de Sódio-Glicose , Tiofenos/química , Animais , Glicemia/análise , Células CHO , Canagliflozina , Linhagem Celular , Cricetinae , Cricetulus , Dieta Hiperlipídica , Glucosídeos/síntese química , Glucosídeos/farmacocinética , Meia-Vida , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Monossacarídeos/síntese química , Monossacarídeos/farmacocinética , Ligação Proteica , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Transportador 1 de Glucose-Sódio/genética , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismoRESUMO
We discovered that C-glucosides 4 bearing a heteroaromatic ring formed metabolically more stable inhibitors for sodium-dependent glucose cotransporter 2 (SGLT2) than the O-glucoside, 2 (T-1095). A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.