RESUMEN
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.
Asunto(s)
Acuaporina 1/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , HumanosRESUMEN
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.
Asunto(s)
Indazoles/síntesis química , Indazoles/uso terapéutico , Hipertensión Ocular/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Administración Tópica , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/uso terapéutico , Benzofenonas/administración & dosificación , Benzofenonas/uso terapéutico , Bromobencenos/administración & dosificación , Bromobencenos/uso terapéutico , Córnea/metabolismo , Glaucoma/tratamiento farmacológico , Células HT29 , Humanos , Técnicas In Vitro , Indazoles/efectos adversos , Indicadores y Reactivos , Presión Intraocular/efectos de los fármacos , Macaca fascicularis , Permeabilidad , Ratas , Receptores Adrenérgicos alfa/metabolismo , Receptores de Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/efectos adversos , Relación Estructura-ActividadRESUMEN
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%.
Asunto(s)
Glaucoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/síntesis química , Pirazinas/uso terapéutico , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Cobayas , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/química , Pirazinas/farmacología , Piridinas/química , Piridinas/farmacología , Piridinas/uso terapéuticoRESUMEN
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.
Asunto(s)
Luz , Traumatismos Experimentales por Radiación/prevención & control , Retina/efectos de la radiación , Degeneración Retiniana/prevención & control , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Animales , Buspirona/farmacología , Adaptación a la Oscuridad , Relación Dosis-Respuesta a Droga , Electrorretinografía , Masculino , Estrés Oxidativo , Piperazinas/farmacología , Piridinas/farmacología , Traumatismos Experimentales por Radiación/etiología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/metabolismo , Retina/efectos de los fármacos , Degeneración Retiniana/etiología , Antagonistas de la Serotonina/farmacologíaRESUMEN
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.
Asunto(s)
Modelos Animales de Enfermedad , Glaucoma/enzimología , Hipertensión Ocular/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Tiofenos/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Glaucoma/fisiopatología , Haplorrinos , Células HeLa , Humanos , Presión Intraocular/efectos de los fármacos , Hipertensión Ocular/fisiopatologíaRESUMEN
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.
Asunto(s)
4-Aminopiridina/análogos & derivados , Antiinflamatorios/química , Cumarinas/química , Inhibidores de Fosfodiesterasa 4 , Agua/química , 4-Aminopiridina/síntesis química , 4-Aminopiridina/química , 4-Aminopiridina/uso terapéutico , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/uso terapéutico , Sitios de Unión , Simulación por Computador , Cumarinas/síntesis química , Cumarinas/uso terapéutico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Modelos Animales de Enfermedad , Síndromes de Ojo Seco/tratamiento farmacológico , Conejos , RatasRESUMEN
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.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Pirazinas/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Glaucoma/tratamiento farmacológico , Glaucoma/enzimología , Haplorrinos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/metabolismo , Pirazinas/uso terapéutico , Conejos , Quinasas Asociadas a rho/metabolismoRESUMEN
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.
Asunto(s)
Oftalmopatías/tratamiento farmacológico , Glaucoma/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Prostaglandinas Sintéticas/farmacología , Administración Tópica , Animales , Gatos , Dinoprost/farmacología , Descubrimiento de Drogas , Glaucoma/complicaciones , Haplorrinos , Presión Intraocular/efectos de los fármacos , Prostaglandinas F Sintéticas/farmacología , Prostaglandinas Sintéticas/efectos adversos , Conejos , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Glaucoma/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Presión Intraocular , Proteínas de la Membrana/fisiología , Proteínas Wnt/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Células Cultivadas , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , ARN Mensajero/análisis , Transducción de Señal , Malla Trabecular/metabolismo , beta Catenina/fisiologíaRESUMEN
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%.
Asunto(s)
Antihipertensivos/química , Antihipertensivos/farmacología , Benzofuranos/química , Benzofuranos/farmacología , Hipertensión Ocular , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Animales , Antihipertensivos/síntesis química , Benzofuranos/síntesis química , Macaca fascicularis , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Ratas , Receptor de Serotonina 5-HT2A/química , Agonistas de Receptores de Serotonina/síntesis química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Glaucoma de Ángulo Abierto/enzimología , Presión Intraocular , Disco Óptico/enzimología , Enfermedades del Nervio Óptico/enzimología , Retina/enzimología , Anciano , Animales , Proteínas de Caenorhabditis elegans/antagonistas & inhibidores , Proteínas de Caenorhabditis elegans/genética , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Perfilación de la Expresión Génica , Guanidinas/farmacología , Humanos , Inmunohistoquímica , Masculino , Hipertensión Ocular/enzimología , Traumatismos del Nervio Óptico/enzimología , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas BNRESUMEN
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.
Asunto(s)
Antihipertensivos/síntesis química , 2,5-Dimetoxi-4-Metilanfetamina/análogos & derivados , 2,5-Dimetoxi-4-Metilanfetamina/síntesis química , Oxígeno/química , Agonistas del Receptor de Serotonina 5-HT2 , 2,5-Dimetoxi-4-Metilanfetamina/química , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Unión Competitiva , Barrera Hematoencefálica , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Aprendizaje Discriminativo/efectos de los fármacos , Presión Intraocular/efectos de los fármacos , Macaca fascicularis , Masculino , Hipertensión Ocular/tratamiento farmacológico , Hipertensión Ocular/fisiopatología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Hipotensión Ocular/tratamiento farmacológico , Prostaglandinas/administración & dosificación , Prostaglandinas/química , Administración Tópica , Animales , Gatos , Haplorrinos , ConejosRESUMEN
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 Asunto(s)
Fluoruros/química
, Hipotensión Ocular/tratamiento farmacológico
, Prostaglandinas/química
, Prostaglandinas/farmacología
, Receptores de Prostaglandina/agonistas
, Administración Tópica
, Animales
, Gatos
, Haplorrinos
, Estructura Molecular
, Prostaglandinas/síntesis química
, Prostaglandinas/metabolismo
, Conejos
, Receptores de Prostaglandina/química
, Receptores de Prostaglandina/metabolismo
RESUMEN
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.
Asunto(s)
Cuerpo Ciliar/metabolismo , Córnea/metabolismo , Dinoprost/análogos & derivados , Dinoprost/biosíntesis , Iris/metabolismo , Metabolismo de los Lípidos , Esclerótica/metabolismo , Amidas , Animales , Bimatoprost , Cromatografía Líquida de Alta Presión , Cloprostenol/análogos & derivados , Humanos , Hidrólisis , Técnicas In Vitro , Lípidos , ConejosRESUMEN
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.
Asunto(s)
Antiinflamatorios/farmacología , Benzopiranos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Naproxeno/farmacología , Amidas , Adhesión Celular/efectos de los fármacos , Preescolar , Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Relación Dosis-Respuesta a Droga , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Ésteres , Humanos , Ácidos Hidroxieicosatetraenoicos/antagonistas & inhibidores , Leucotrieno B4/antagonistas & inhibidores , Masculino , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/inmunología , Activación Neutrófila , Células U937RESUMEN
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.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/uso terapéutico , Hipertensión Ocular/tratamiento farmacológico , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/uso terapéutico , Agonistas de Receptores de Serotonina/uso terapéutico , Animales , Células CHO , Cricetinae , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Ligandos , Macaca fascicularis , Masculino , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , TransfecciónRESUMEN
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.
Asunto(s)
Antihipertensivos/uso terapéutico , Cloprostenol/análogos & derivados , Cloprostenol/uso terapéutico , Dinoprost/uso terapéutico , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Presión Intraocular/efectos de los fármacos , Receptores de Prostaglandina/agonistas , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Humor Acuoso/efectos de los fármacos , Gatos , Cloprostenol/química , Cloprostenol/farmacología , Dinoprost/análogos & derivados , Dinoprost/química , Dinoprost/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Cobayas , Humanos , Macaca fascicularis , Masculino , Hipertensión Ocular/tratamiento farmacológico , Conejos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Inmunológicos , Seguridad , Relación Estructura-Actividad , Timolol/uso terapéutico , TravoprostRESUMEN
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.