RESUMO
Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicochemical and permeability profile, subsequently identified cardiovascular side effects in multiple species precluded further clinical evaluation of this compound. Herein, we report selected structural modifications that resulted in the identification of (8R)-1-[(2S)-2-aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol (13), which displayed an acceptable profile to support advancement for further preclinical evaluation as a candidate for proof-of-concept studies in humans.
Assuntos
Indazóis/síntese química , Indazóis/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Administração Tópica , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Benzofenonas/administração & dosagem , Benzofenonas/uso terapêutico , Bromobenzenos/administração & dosagem , Bromobenzenos/uso terapêutico , Córnea/metabolismo , Glaucoma/tratamento farmacológico , Células HT29 , Humanos , Técnicas In Vitro , Indazóis/efeitos adversos , Indicadores e Reagentes , Pressão Intraocular/efeitos dos fármacos , Macaca fascicularis , Permeabilidade , Ratos , Receptores Adrenérgicos alfa/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Relação Estrutura-AtividadeRESUMO
A series of 2,3,6-pyrazine Rho Kinase inhibitors were optimized for in vivo activity for topical ocular dosing. Modifications of the 2-(piperazin-1-yl)pyrazine derivatives produced compounds with improved solubility and physicochemical properties. Modifications of the 6-pyrazine substituent led to improvements in in vitro potency. Compound 9 had the best in vitro and in vivo potency of EC50=260 nM with a 30% reduction of IOP in a non-human primate model at a dose of 0.33%.
Assuntos
Glaucoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/síntese química , Pirazinas/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cobaias , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Piridinas/uso terapêuticoRESUMO
AL-38022A is a novel synthetic serotonergic (5-HT) ligand that exhibited high affinity for each of the 5-HT2 receptor subtypes (Ki
Assuntos
Benzopiranos/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Indazóis/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , 2,5-Dimetoxi-4-Metilanfetamina/farmacologia , Agonistas de Receptores Adrenérgicos beta 2 , Animais , Sinalização do Cálcio/efeitos dos fármacos , Físico-Química , Clonagem Molecular , AMP Cíclico/biossíntese , AMP Cíclico/genética , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Fluorbenzenos/farmacologia , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/química , Estômago/efeitos dos fármacosRESUMO
Thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides, which have a quaternary ammonium moiety incorporated into their structures, were synthesized. All of the quaternary ammonium salts prepared in the present study are potent inhibitors of both human carbonic anhydrase-II and recombinant human carbonic anhydrase-IV; they are significantly more potent as inhibitors of these carbonic anhydrase isozymes than the previously reported inhibitor quaternary ammonium homosulfanilamide. By virtue of the permanent cationic charge on these compounds they are anticipated to be membrane-impermeable inhibitors of carbonic anhydrase. Spiro quaternary ammonium compounds, such as 15 and 16, when formed by intracellular cyclization following transport of a suitable precursor molecule, such as 14, may be selective prolonged inhibitors of cytosolic carbonic anhydrase due to intracellular entrapment.
Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica IV/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Óxidos/química , Compostos de Amônio Quaternário/química , Sulfonamidas/química , Anidrase Carbônica II/genética , Anidrase Carbônica IV/genética , Inibidores da Anidrase Carbônica/farmacologia , Membrana Celular/enzimologia , Células Cultivadas , Humanos , Estrutura Molecular , Óxidos/farmacologia , Compostos de Amônio Quaternário/farmacologia , Sulfonamidas/farmacologia , Tiazinas/química , Tiazinas/farmacologiaRESUMO
Serotonin 5-HT2 receptor agonists have recently been shown to be effective in lowering intraocular pressure in nonhuman primates and represent a potential new class of antiglaucoma agents. As part of an effort to identify new selective agonists at this receptor, we have found that (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole (AL-37350A, 11) has high affinity and selectivity (>1000-fold) for the 5-HT(2) receptor relative to other 5-HT receptors. More specifically, 11 is a potent agonist at the 5-HT2A receptor (EC50 = 28.6 nM, E(max) = 103%) that is comparable to serotonin. Evaluation of 11 in conscious ocular hypertensive cynomolgus monkeys showed this compound to be efficacious in reducing intraocular pressure (13.1 mmHg, -37%). Thus, 11 is a potent full agonist with selectivity for the 5-HT2 receptor and is anticipated to serve as a useful tool in exploring the role of the 5-HT2 receptor and its effector system in controlling intraocular pressure.