- Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4-Dihydropyrazino[1,2-b]indazol-1(2H)-one Derivatives
-
Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α1) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2-alkyl-indazole-amide derivatives. This study identified a 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivative with potent serotonin 2A receptor antagonism, >100-fold selectivity over other serotonin subtype receptors, and high affinity for the α1 receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action in vivo relative to the clinically used reference compound timolol.
- Furlotti, Guido,Alisi, Maria Alessandra,Cazzolla, Nicola,Ceccacci, Francesca,Garrone, Beatrice,Gasperi, Tecla,La Bella, Angela,Leonelli, Francesca,Loreto, Maria Antonietta,Magarò, Gabriele,Mangano, Giorgina,Bettolo, Rinaldo Marini,Masini, Emanuela,Miceli, Martina,Migneco, Luisa Maria,Vitiello, Marco
-
supporting information
p. 1597 - 1607
(2018/07/30)
-
- Efficient syntheses of exo-granisetron hydrochloride and other potential impurities present in granisetron hydrochloride, an anti-emetic drug
-
European Pharmacopeia mentions about nine potential impurities in Granisetron hydrochloride. These impurities need to be controlled in the API as described in the Pharmacopeia. Elegant syntheses of four potential impurities in Granisetron hydrochloride are disclosed.
- Vishnu, Eda V.R.,Joseph, Suju,Srinivasana, Abayee K.,Gania, Ramesh S.,Reddy, Govindabur R.,Rao, Patakokila V.,Dahanukara, Vilas H.,Ramanatham, Josyula,Devanna, Nayakanti
-
p. 722 - 727
(2012/05/04)
-
- 2 -ALKYL- INDAZOLE COMPOUNDS FOR THE TREATMENT OF CERTAIN CNS-RELATED DISORDERS
-
2-Alkyl-indazole compound and its pharmaceutically acceptable salts of acid addition, method and intermediates for preparing them, a pharmaceutical composition containing them and use of the latter. The 2-alkyl-indazole compound has the following general formula (I) in which R1, R2, R3, R4, R6, R7, X, Y, W, n, p, and m have the meanings stated in the description.
- -
-
Page/Page column 21
(2008/12/05)
-
- 5-Hydroxytryptamine (5-HT3) Receptor Antagonists. 1. Indazole and Indolizine-3-carboxylic Acid Derivatives
-
Metoclopramide (1) is a gastric motility stimulant and a weak dopamine and 5-HT3 receptor antagonist.Conformational restriction of the (diethylamino)ethyl side chain of 1 in the form of the azabicyclic tropane gave 3, a very potent gastric motility stimulant and 5-HT3 receptor antagonist but devoid of significant dopamine receptor antagonist properties.Subsequent alteration of the aromatic nucleus led to the identification of indazoles 6a-h, and 1- and 3-indolizines 7b-d, and 8, and imidazopyridines 9 and 10, as potent 5-HT3 receptor antagonists devoid ofeither dopamine antagonist or gastric motility stimulatory properties.Further conformational restriction of the side chain identified quinuclidine 11 and isoquinuclidine 12 as potent 5-HT3 receptor antagonists which mimic the distorted chair conformation of the tropane with, in the case of 11, the N-methyl group axial.From these series, 6g (BRL 43694) was found to be both potent and selective and has been shown to be a very effective antiemetic agent against cytotoxic drug induced emesis both in the ferret and in man.
- Bermudez, Jose,Fake, Charles S.,Joiner, Graham F.,Joiner, Karen A.,King, Frank D.,et al.
-
p. 1924 - 1929
(2007/10/02)
-