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1 General aspects (0)   1.1 Epidemiology (9)   1.2 Population genetics (1)   1.3 Pathogenesis (0)   1.4 Quality of life (11)   1.5 Glaucomas as cause of blindness (11)   1.6 Prevention and screening (13) 2 Anatomical structures in glaucoma (0)   2.1 Conjunctiva (2)   2.2 Cornea (14)   2.3 Sclera (8)   2.4 Anterior chamber angle (3)   2.5 Meshwork (0)     2.5.1 Trabecular meshwork (6)     2.5.2 Schlemms canal (3)     2.5.3 Scleral outlet channels (1)   2.6 Aqueous humor dynamics (0)     2.6.1 Production (0)     2.6.2 Outflow (1)       2.6.2.1 Trabecular meshwork (3)       2.6.2.2 Uveoscleral (0)     2.6.3 Compostion (1)   2.7 Episcleral veins and venous pressure (0)   2.8 Iris (6)   2.9 Ciliary body (0)   2.10 Lens (0)   2.11 Vitreous body (1)   2.12 Choroid, peripapillary choroid, peripapillary atrophy (2)   2.13 Retina and retinal nerve fibre layer (21)   2.14 Optic disc (20)   2.15 Optic nerve (4)   2.16 Chiasma and retrochiasmal central nervous system (4)   2.17 Stem cells (3)   2.20 Other (0) 3 Laboratory methods (0)   3.1 Microscopy (0)   3.2 Electron microscopy (1)   3.3 Immunohistochemistry (0)   3.4 Molecular genetics (0)     3.4.1 Linkage studies (1)     3.4.2 Gene studies (14)   3.5 Molecular biology incl. SiRNA (10)   3.6 Cellular biology (23)   3.7 Biochemistry (6)   3.8 Pharmacology (12)   3.9 Pathophysiology (9)   3.10 Immunobiology (6)   3.11 Pharmacogenetics (0)   3.12 Proteomics (0)   3.13 In vivo imaging (0)     3.13.1 Laser Scanning (0)       3.13.1.1 Confocal Scanning Laser Ophthalmoscopy (0)       3.13.1.2 Confocal Scanning Laser Polarimetry (0)     3.13.2 Optical Coherence Tomography (0)       3.13.2.1 Anterior Segment (0)       3.13.2.2 Posterior Segment (0)     3.13.3 RGC Imaging (1)     3.13.4 Other (0)   3.20 Other (1) 4 Tissue culture of ocular cells (0) 5 Experimental glaucoma; animal models (0)   5.1 Rodent (12)   5.2 Primates (2)   5.3 Other (8) 6 Clinical examination methods (0)   6.1 Intraocular pressure measurement; factors affecting IOP (1)     6.1.1 Devices, techniques (13)     6.1.2 Fluctuation, circadian rhythms (8)     6.1.3 Factors affecting IOP (15)   6.2 Tonography, aqueous flow measurement (see also 2.6) (1)   6.3 Biomicroscopy (slitlamp) (0)     6.3.1 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8 Refractive errors in relation to glaucoma (0)   8.1 Myopia (9)   8.2 Hypermetropia (0)   8.3 Contact lenses (0)   8.4 Refractive surgical procedures (0)   8.5 Other (0) 9 Clinical forms of glaucomas (0)   9.1 Developmental glaucomas (0)     9.1.1 Congenital glaucoma, Buphthalmos (8)     9.1.2 Juvenile glaucoma (10)     9.1.3 Syndromes of Axenfeld, Rieger, Peters, aniridia (2)     9.1.4 Other (1)   9.2 Primary open angle glaucomas (0)     9.2.1 Ocular hypertension (3)     9.2.2 Other risk factors for glaucoma (8)     9.2.3 Open angle glaucoma with elevated IOP (0)     9.2.4 Normal pressure glaucoma (12)   9.3 Primary angle closure glaucomas (0)     9.3.1 Acute primary angle closure glaucoma (pupillary block) (9)     9.3.2 Chronic primary angle closure glaucoma (pupillary block) (4)     9.3.3 Plateau iris syndrome (0)     9.3.4 Primary angle closure suspect (0)     9.3.5 Primary angle closure (4)     9.3.10 Other (0)   9.4 Glaucomas associated with other ocular and systemic disorders 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associated with intraocular tumors (5)     9.4.9 Glaucomas associated with elevated episcleral venous pressure (1)       9.4.10 Glaucomas associated with hemorrhage (4)     9.4.11 Glaucomas following intraocular surgery (2)       9.4.11.1 Ciliary block (malignant) glaucoma (1)       9.4.11.2 Glaucomas in aphakia and pseudophakia (6)       9.4.11.3 Epithelial, fibrous, and endothelial proliferation (0)       9.4.11.4 Glaucomas associated with corneal surgery (8)       9.4.11.5 Glaucomas associated with vitreoretinal surgery (2)     9.4.15 Glaucoma in relation to systemic disease (21)     9.4.20 Other (2) 10 Differential diagnosis e.g. anterior and posterior ischemic optic neuropathy (1) 11 Medical treatment (0)   11.1 General management, indication (9)   11.2 Cholinergic drugs (1)   11.3 Adrenergic drugs (0)     11.3.1 Epinephrine (0)     11.3.2 Thymoxamine, dapiprazole (0)     11.3.3 Apraclonidine, brimonidine (0)     11.3.4 Betablocker (3)     11.3.5 Other (0)   11.4 Prostaglandins 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    12.8.1 Without tube implant (22)     12.8.2 With tube implant or other drainage devices (25)     12.8.3 Non-perforating (4)     12.8.4 Using laser (0)     12.8.5 Other (1)     12.8.10 Woundhealing antifibrosis (15)     12.8.11 Complications, endophthalmitis (7)   12.9 Trabeculotomy, goniotomy (10)   12.10 Cyclodestruction (5)   12.11 Cyclodialysis (0)   12.12 Cataract extraction (0)     12.12.1 Intracapsular (0)     12.12.2 Extracapsular (0)     12.12.3 Phacoemulsification (7)   12.14 Combined cataract extraction and glaucoma surgery (0)     12.14.1 Intracapsular (0)     12.14.2 Extracapsular (0)     12.14.3 Phacoemulsification (6)   12.15 Capsulotomy (0)   12.16 Vitrectomy (5)   12.17 Anesthesia (2)   12.20 Other (2) 13 Therapeutic prognosis and outcome (0)   13.1 Prognostic factors (1)   13.2 Outcome (0)     13.2.1 IOP (1)     13.2.2 Visual field (0)       13.2.2.1 Progression (0)       13.2.2.2 Improvement (0)     13.2.3 Other (0) 14 Costing studies; pharmacoeconomics (5) 15 Miscellaneous (27)

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Abstract #65953 Published in IGR 17-3

Ocular Hypotensive Response in Nonhuman Primates of (8R)-1-(2S)-2-Aminopropyl-8,9-dihydro-7H-pyrano2,3-gindazol-8-ol a Selective 5-HT2 Receptor Agonist

May JA; Sharif NA; McLaughlin MA; Chen HH; Severns BS; Kelly CR; Holt WF; Young R; Glennon RA; Hellberg MR; Dean TR
Journal of Medicinal Chemistry 2015; 58: 8818-8833

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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.

Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.

Full article

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Classification:

3.8 Pharmacology (Part of: 3 Laboratory methods)
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
5.2 Primates (Part of: 5 Experimental glaucoma; animal models)

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