RESUMO
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
Elevated intraocular pressure (IOP) is the principal risk factor for glaucoma and results from excessive impedance of the fluid outflow from the eye. This abnormality likely originates from outflow pathway tissues such as the trabecular meshwork (TM), but the associated molecular etiology is poorly understood. We discovered what we believe to be a novel role for secreted frizzled-related protein-1 (sFRP-1), an antagonist of Wnt signaling, in regulating IOP. sFRP1 was overexpressed in human glaucomatous TM cells. Genes involved in the Wnt signaling pathway were expressed in cultured TM cells and human TM tissues. Addition of recombinant sFRP-1 to ex vivo perfusion-cultured human eyes decreased outflow facility, concomitant with reduced levels of beta-catenin, the Wnt signaling mediator, in the TM. Intravitreal injection of an adenoviral vector encoding sFRP1 in mice produced a titer-dependent increase in IOP. Five days after vector injection, IOP increased 2 fold, which was significantly reduced by topical ocular administration of an inhibitor of a downstream suppressor of Wnt signaling. Thus, these data indicate that increased expression of sFRP1 in the TM appears to be responsible for elevated IOP in glaucoma and restoring Wnt signaling in the TM may be a novel disease intervention strategy for treating glaucoma.
Assuntos
Glaucoma/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Pressão Intraocular , Proteínas de Membrana/fisiologia , Proteínas Wnt/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Células Cultivadas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , RNA Mensageiro/análise , Transdução de Sinais , Malha Trabecular/metabolismo , beta Catenina/fisiologiaRESUMO
Inhibition of rho kinase (ROCK) has been recognized as an important target for a number of diseases, including glaucoma. Herein we report SAR development around two hits from a kinase library that led to the discovery of the ROCK inhibitor compound 38. In vitro and in vivo analysis of this compound, including its effects in a monkey model of glaucoma will be discussed.
Assuntos
Inibidores de Proteínas Quinases/química , Pirazinas/química , Quinases Associadas a rho/antagonistas & inibidores , Animais , Glaucoma/tratamento farmacológico , Glaucoma/enzimologia , Haplorrinos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/metabolismo , Pirazinas/uso terapêutico , Coelhos , Quinases Associadas a rho/metabolismoRESUMO
We identified a new benzothiophene containing Rho kinase inhibitor scaffold in an ultra high-throughput enzymatic activity screen. SAR studies, driven by a novel label-free cellular impedance assay, were used to derive 39, which substantially reduced intraocular pressure in a monkey model of glaucoma-associated ocular hypertension.
Assuntos
Modelos Animais de Doenças , Glaucoma/enzimologia , Hipertensão Ocular/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Tiofenos/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Glaucoma/fisiopatologia , Haplorrinos , Células HeLa , Humanos , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/fisiopatologiaRESUMO
PDE4 inhibitors have the potential to alleviate the symptoms and underlying inflammation associated with dry eye. Disclosed herein is the development of a novel series of water-soluble PDE4 inhibitors. Our studies led to the discovery of coumarin 18, which is effective in a rabbit model of dry eye and a tear secretion test in rats.
Assuntos
4-Aminopiridina/análogos & derivados , Anti-Inflamatórios/química , Cumarínicos/química , Inibidores da Fosfodiesterase 4 , Água/química , 4-Aminopiridina/síntese química , 4-Aminopiridina/química , 4-Aminopiridina/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/uso terapêutico , Sítios de Ligação , Simulação por Computador , Cumarínicos/síntese química , Cumarínicos/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Modelos Animais de Doenças , Síndromes do Olho Seco/tratamento farmacológico , Coelhos , RatosRESUMO
FP-Class prostaglandin analogs have demonstrated utility for the treatment of glaucoma and ocular hypertension. A series of novel FP prostaglandin analogs was designed to optimize topical ocular activity and reduce ocular side-effects by replacing 13-carbon with oxygen. A facile synthesis was successfully developed for synthesis of the 13-oxa prostaglandins from the commercially available Corey aldehyde benzoate. Among the compounds synthesized, AL-16082 was the most potent prostaglandin FP agonist in vitro. In a prostaglandin FP receptor-linked second-messenger assay, phosphoinositide (PI) turnover, it exhibited a potency value (EC(50)) of 1.9 nM (78% max. response relative to fluprostenol). The isopropyl ester of AL-16082, compound AL-16049, significantly lowered intraocular pressure (IOP) in the ocular hypertensive monkey eyes by 30%. In the study of acute ocular irritation response in New Zealand albino rabbits, AL-16049 produced lower incidence of hyperemia, swelling, and discharge than PGF(2alpha) (1 microg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 microg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.
Assuntos
Oftalmopatias/tratamento farmacológico , Glaucoma/tratamento farmacológico , Hipertensão/tratamento farmacológico , Prostaglandinas Sintéticas/farmacologia , Administração Tópica , Animais , Gatos , Dinoprosta/farmacologia , Descoberta de Drogas , Glaucoma/complicações , Haplorrinos , Pressão Intraocular/efeitos dos fármacos , Prostaglandinas F Sintéticas/farmacologia , Prostaglandinas Sintéticas/efeitos adversos , Coelhos , Relação Estrutura-AtividadeRESUMO
Aquaporins (AQPs) are a family of membrane proteins that function as channels facilitating water transport in response to osmotic gradients. These play critical roles in several normal physiological and pathological states and are targets for drug discovery. Selective inhibition of the AQP1 water channel may provide a new approach for the treatment of several disorders including ocular hypertension/glaucoma, congestive heart failure, brain swelling associated with a stroke, corneal and macular edema, pulmonary edema, and otic disorders such as hearing loss and vertigo. We developed a high-throughput assay to screen a library of compounds as potential AQP1 modulators by monitoring the fluorescence dequenching of entrapped calcein in a confluent layer of AQP1-overexpressing CHO cells that were exposed to a hypotonic shock. Promising candidates were tested in a Xenopus oocyte-swelling assay, which confirmed the identification of two lead classes of compounds belonging to aromatic sulfonamides and dihydrobenzofurans with IC50 s in the low micromolar range. These selected compounds directly inhibited water transport in AQP1-enriched stripped erythrocyte ghosts and in proteoliposomes reconstituted with purified AQP1. Validation of these lead compounds, by the three independent assays, establishes a set of attractive AQP1 blockers for developing novel, small-molecule functional modulators of human AQP1.
Assuntos
Aquaporina 1/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , HumanosRESUMO
PURPOSE: To determine whether inducible nitric oxide synthase (NOS-2) is involved in glaucomatous optic neuropathy. METHODS: Chronic elevation of rat intraocular pressure (IOP) leading to optic nerve damage was induced by episcleral injection of hypertonic saline, which caused sclerosis and blockade of aqueous humor outflow pathways. Expression of NOS-2 in the retina and optic nerve head (ONH) was evaluated by immunohistochemistry, gene array analysis, and quantitative PCR (Q-PCR). Immunohistochemistry was also used to assess the NOS-2 level in the ONH from primary open-angle glaucoma (POAG) and nonglaucomatous human eyes. Finally, an NOS-2 inhibitor, aminoguanidine, administered orally in the drinking water, was tested for its effect on optic nerve injury in rats with ocular hypertension. RESULTS: Chronically elevated IOP in the rat produced optic nerve damage that correlated with pressure change (r(2) = 0.77), but did not increase NOS-2 immunoreactivity in the optic nerve, ONH, or ganglion cell layer. Retinal and ONH NOS-2 mRNA levels did not correlate with either IOP level or severity of optic nerve injury. Similarly, there was no difference in NOS-2 immunoreactivity in the optic nerve or ONH between POAG and nonglaucomatous eyes. Furthermore, aminoguanidine treatment did not affect the development of pressure-induced optic neuropathy in the rat. CONCLUSIONS: As demonstrated by several independent methods, glaucomatous optic neuropathy was not associated with a significant change in the expression of NOS-2 in the retina, ONH, or optic nerve.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Glaucoma de Ângulo Aberto/enzimologia , Pressão Intraocular , Disco Óptico/enzimologia , Doenças do Nervo Óptico/enzimologia , Retina/enzimologia , Idoso , Animais , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Caenorhabditis elegans/genética , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Perfilação da Expressão Gênica , Guanidinas/farmacologia , Humanos , Imuno-Histoquímica , Masculino , Hipertensão Ocular/enzimologia , Traumatismos do Nervo Óptico/enzimologia , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos BNRESUMO
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
Activation of 5-HT(2A) serotonin receptors represents a novel approach to lowering intraocular pressure. Because 5-HT(2A) serotonin receptor agonists might also produce undesirable central effects should sufficient quantities enter the brain, attempts were made to identify 5-HT(2) serotonin receptor agonists with reduced propensity to penetrate the blood-brain barrier. 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropan-1-ol (6), an analogue of the 5-HT(2) serotonin receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB; 1a) bearing a benzylic hydroxyl group, was identified as a candidate structure. Of the four optical isomers of 6, the 1R,2R-isomer (6d; K(i) = 0.5 nM) was found to bind at 5-HT(2A) receptors with an affinity similar to that of R(-)DOB (K(i) = 0.2 nM). Like R(-)DOB, 6d behaved as a partial agonist (efficacy ca. 50%) in a 5-HT(2)-mediated calcium mobilization assay. However, in an in vivo test of central action (i.e., stimulus generalization with rats as subjects), 6d was >15 times less potent than R(-)DOB. O-Methylation of 6d (i.e., 7d; 5-HT(2A) K(i) = 0.3 nM) resulted in an agent that behaved as a full (93% efficacy) agonist. Intraocular administration of 300 microg of 6d and 7d to ocular hypertensive monkeys was shown to reduce intraocular pressure by 20-27%. Given the route of administration (i.e., topical), and concentrations necessary to reduce intraocular pressure, compounds such as 6d should demonstrate minimal central effects at potentially useful therapeutic doses and offer useful leads for further development.
Assuntos
Anti-Hipertensivos/síntese química , 2,5-Dimetoxi-4-Metilanfetamina/análogos & derivados , 2,5-Dimetoxi-4-Metilanfetamina/síntese química , Oxigênio/química , Agonistas do Receptor 5-HT2 de Serotonina , 2,5-Dimetoxi-4-Metilanfetamina/química , 2,5-Dimetoxi-4-Metilanfetamina/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Ligação Competitiva , Barreira Hematoencefálica , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Aprendizagem por Discriminação/efeitos dos fármacos , Pressão Intraocular/efeitos dos fármacos , Macaca fascicularis , Masculino , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/fisiopatologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The structure-activity studies that led to the identification of travoprost, a highly selective and potent FP prostaglandin analog, and AL-6598, a DP prostaglandin analog, are detailed. In both series, the 1-alcohol analogs are very effective and are thought to be acting as prodrugs for the biologically active carboxylic acids. The efficacy of amide prodrugs depends on the degree of substitution and the size of the substituents. Selected compounds are profiled in vitro and in vivo preclinically. Clinical studies show that travoprost 0.004% (isopropyl ester) provided intraocular pressure control superior to timolol 0.5% when used as monotherapy in patients with open-angle glaucoma or ocular hypertension. In clinical studies, AL-6598 0.01% provided a sustained intraocular pressure reduction with q.d. application; b.i.d. provided greater intraocular pressure control. The acute and, apparently, conjunctival hyperemia associated with topical ocular AL-6598 can be attenuated while maintaining intraocular pressure-lowering efficacy by formulating with brimonidine.
Assuntos
Anti-Hipertensivos/uso terapêutico , Cloprostenol/análogos & derivados , Cloprostenol/uso terapêutico , Dinoprosta/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Receptores de Prostaglandina/agonistas , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Humor Aquoso/efeitos dos fármacos , Gatos , Cloprostenol/química , Cloprostenol/farmacologia , Dinoprosta/análogos & derivados , Dinoprosta/química , Dinoprosta/farmacologia , Relação Dose-Resposta a Droga , Feminino , Cobaias , Humanos , Macaca fascicularis , Masculino , Hipertensão Ocular/tratamento farmacológico , Coelhos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Imunológicos , Segurança , Relação Estrutura-Atividade , Timolol/uso terapêutico , TravoprostRESUMO
Selected ester- (AL-5898 and AL-8417) and amide-linked benzopyran analogues (AL-7538 and AL-12615) were evaluated in vitro for their ability to inhibit key enzymes/processes of the inflammatory response. AL-7538 and AL-12615 exhibited weak intrinsic cyclooxygenase inhibitory activity (IC50 = 13 microM, 37 microM). In contrast, 5-HETE and LTB4 synthesis in A(23187)-stimulated neutrophils was effectively inhibited by both ester and amide analogs (IC50 = 2-3 microM). While there was some indication for differing sensitivities among benzopyran esters and amides in the suppression of cytokine synthesis in stimulated U-937 cells, there appeared to be no great discrimination when assessing their effect on U-937 cell adhesion to IL-1beta activated HMVEC-L cells. Inhibition of cell adhesion was concentration-dependent, with IC50 values ranging between 18 microM and 30 microM for AL-5898. Concentration-dependent inhibition of inflammatory cytokine production (i.e., IL-1beta, TNF-alpha, GM-CSF and IL-6) was also apparent in LPS-stimulated, cultured PBMC as well as in PMA/A(23187) activated U-937 cells monitoring the synthesis of IL-1beta, IL-8, TNF-alpha, and MCP-1. Notably, the hydrolysis products of the benzopyranyl ester, AL-5692 and (S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, were devoid of pharmacological activity when assessed for inhibition of monocyte adhesion or IL-1beta synthesis. Collectively, our data demonstrate the unique in vitro polypharmacology of a novel series of benzopyran analogs that suppress pivotal enzymes and processes in the inflammatory response.
Assuntos
Anti-Inflamatórios/farmacologia , Benzopiranos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Naproxeno/farmacologia , Amidas , Adesão Celular/efeitos dos fármacos , Pré-Escolar , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Ésteres , Humanos , Ácidos Hidroxieicosatetraenoicos/antagonistas & inibidores , Leucotrieno B4/antagonistas & inibidores , Masculino , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Ativação de Neutrófilo , Células U937RESUMO
Bimatoprost (Lumigan), the ethyl amide derivative of the potent prostaglandin FP agonist 17-phenyl-trinor PGF(2alpha), has been reported to be a member of a pharmacologically unique class of ocular hypotensive agents. To confirm that bimatoprost, which is intrinsically active as an FP prostaglandin agonist, is also a prostaglandin analog prodrug, the hydrolysis of bimatoprost by ocular tissues was studied by incubating solutions containing bimatoprost with either human or rabbit ocular tissue. The ethyl amide group of bimatoprost was hydrolyzed by rabbit and human cornea, iris/ciliary body and Thasclera to produce the expected carboxylic acid product, 17-phenyl-trinor PGF(2alpha). The rate of hydrolysis by human and rabbit cornea and iris/ciliary body is similar, whereas the rate of hydrolysis by the sclera is slower in humans than in rabbits. These studies show that human and rabbit ocular tissue (cornea, iris/ciliary body and sclera) can convert bimatoprost to the potent prostaglandin FP agonist 17-phenyl-trinor PGF(2alpha). Separate in vitro studies clearly show that both bimatoprost and 17-phenyl-trinor PGF(2alpha) have affinity for and are agonists at the human FP receptor. Taken together, the data strongly suggests that the ocular hypotensive effect of bimatoprost can be attributed to its activity as a prostaglandin receptor agonist either directly or through its role as a prostaglandin agonist prodrug.
Assuntos
Corpo Ciliar/metabolismo , Córnea/metabolismo , Dinoprosta/análogos & derivados , Dinoprosta/biossíntese , Iris/metabolismo , Metabolismo dos Lipídeos , Esclera/metabolismo , Amidas , Animais , Bimatoprost , Cromatografia Líquida de Alta Pressão , Cloprostenol/análogos & derivados , Humanos , Hidrólise , Técnicas In Vitro , Lipídeos , CoelhosRESUMO
PURPOSE: 5-HT(1A) agonists are neuroprotective in CNS injury models. The authors evaluated the efficacy of 5-HT(1A) agonists to protect the retina from severe blue light-induced photo-oxidative damage. METHODS: Albino rats were dosed (subcutaneously) with AL-8309A, 8-OH DPAT, or buspirone once or three times before 6-hour exposure to blue light. Electroretinograms (ERGs) were measured to assess retinal function, and retinal damage was evaluated by light microscopy. Topical ocular dosing with 1.75% AL-8309B was also evaluated. Rats were dosed with WAY-100635, a 5-HT(1A) antagonist, to determine whether protection required activation of the 5-HT(1A) receptor. RESULTS: ERG response amplitudes were significantly (P < 0.05) depressed more than 66% in vehicle-dosed rats after light exposure. ERGs were significantly higher in rats treated with AL-8309A (0.1-30 mg/kg), 8-OH DPAT (0.1-1 mg/kg), buspirone (5-20 mg/kg) or topical ocular with 1.75% AL-8309B. Retinas from AL-8309A and 8-OH DPAT-treated rats were devoid of histologic lesions. Significant protection was measured in rats dosed once 0, 24, or 48 hours before light exposure. Protection provided by dosing with AL-8309B or 8-OH DPAT was inhibited in rats predosed with WAY-100635. CONCLUSIONS: 5-HT(1A) agonists provided potent and complete functional and structural protection. Protection was inhibited by treatment with WAY-100635, confirming the requirement for activating the 5-HT(1A) receptor in initiating this survival pathway. Single-dose experiments with AL-8309A suggest that the mechanism of protection is rapidly activated and protection persists for 48 hours. AL-8309B (1.75%) was effective after topical ocular dosing. AL-8309B is under evaluation in the clinic and may be useful in treating age-related macular degeneration.
Assuntos
Luz , Lesões Experimentais por Radiação/prevenção & controle , Retina/efeitos da radiação , Degeneração Retiniana/prevenção & controle , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Buspirona/farmacologia , Adaptação à Escuridão , Relação Dose-Resposta a Droga , Eletrorretinografia , Masculino , Estresse Oxidativo , Piperazinas/farmacologia , Piridinas/farmacologia , Lesões Experimentais por Radiação/etiologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Retina/efeitos dos fármacos , Degeneração Retiniana/etiologia , Antagonistas da Serotonina/farmacologiaRESUMO
A series of 8-substituted benzodifuran analogs was prepared and evaluated for 5-HT(2A) receptor binding and activation. Several compounds containing ether and ester functionality were found to be potent agonists. Topical ocular administration of 5, 18, and 25 effectively reduced intra-ocular pressure in the hypertensive cynomolgus monkey eye in the range of 25-37%.
Assuntos
Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Hipertensão Ocular , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Animais , Anti-Hipertensivos/síntese química , Benzofuranos/síntese química , Macaca fascicularis , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Receptor 5-HT2A de Serotonina/química , Agonistas do Receptor de Serotonina/síntese química , Relação Estrutura-AtividadeRESUMO
A novel series of 15-fluoro prostaglandins with phenoxy termination of the omega-chain was synthesized and evaluated for binding and functional activation of the prostaglandin FP receptor in vitro and for side effect potential and topical ocular hypotensive efficacy in vivo. Compounds with the 15alpha-fluoride relative stereochemistry displayed EC50 values of Assuntos
Fluoretos/química
, Hipotensão Ocular/tratamento farmacológico
, Prostaglandinas/química
, Prostaglandinas/farmacologia
, Receptores de Prostaglandina/agonistas
, Administração Tópica
, Animais
, Gatos
, Haplorrinos
, Estrutura Molecular
, Prostaglandinas/síntese química
, Prostaglandinas/metabolismo
, Coelhos
, Receptores de Prostaglandina/química
, Receptores de Prostaglandina/metabolismo
RESUMO
Published investigations of serotonin-1A (5-hydroxytryptamine1A; 5-HT1A) receptor agonists and serotonin-2A (5-hydroxytryptamine2A; 5-HT2A) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressure-lowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT1A agonists and 5-HT2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT2 receptor antagonists [e.g., R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M-100907) and 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide (SB-242084)] lowered intraocular pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT1A and 5-HT2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-alpha-methyltryptamine, 5-methoxy-alpha-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT2 receptor agonist R-(-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Células CHO , Cricetinae , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Ligantes , Macaca fascicularis , Masculino , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , TransfecçãoRESUMO
A series of 11-oxa prostaglandin analogs was evaluated for FP receptor binding and activation. Several compounds having aryloxy-terminated lower chains were found to be potent agonists. Topical ocular dosing of AL-12182, the isopropyl ester prodrug of the potent agonist 13, lowered intraocular pressure in the monkey by 40% accompanied by minimal conjunctival hyperemia in the rabbit. AL-12182 was synthesized on multigram scale starting with D-sorbitol.
Assuntos
Hipotensão Ocular/tratamento farmacológico , Prostaglandinas/administração & dosagem , Prostaglandinas/química , Administração Tópica , Animais , Gatos , Haplorrinos , CoelhosRESUMO
A series of prostaglandin DP agonists containing a 3-oxa-15-cyclohexyl motif was synthesized and evaluated in several in vitro and in vivo biological assays. The reference compound ZK 118.182 (9beta-chloro-15-cyclohexyl-3-oxa-omega-pentanor PGF(2alpha)) is a potent full agonist at the prostaglandin DP receptor. Saturation of the 13,14 olefin affords AL-6556, which is less potent but is still a full agonist. Replacement of the 9-chlorine with a hydrogen atom or inversion of the carbon 15 stereochemistry also reduces affinity. In in vivo studies ZK 118.182 lowers intraocular pressure (IOP) upon topical application in the ocular hypertensive monkey. Ester, 1-alcohol, and selected amide prodrugs of the carboxylic acid enhance in vivo potency, presumably by increasing bioavailability. The clinical candidate AL-6598, the isopropyl ester prodrug of AL-6556, produces a maximum 53% drop in monkey IOP with a 1 microg dose (0.003% w/w) using a twice-daily dosing regime. Synthetically, AL-6598 was accessed from known intermediate 1 using a novel key sequence to install the cis allyl ether in the alpha chain, involving a selective Swern oxidative desilylation of a primary silyl ether in the presence of a secondary silyl ether. In this manner, 136 g of AL-6598 was synthesized under GMP conditions for evaluation in phase I clinical trials.