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, causing optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and nowadays, the key therapeutic target of the existing pharmacological treatments. We studied, as potential ocular hypotensive agents, compounds acting on two receptors (serotonin 2A, 5-HT2A, and adrenergic α1) linked to the regulation of the humour aqueous dynamic. In this article we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic 2N-alkyl-indazole-amide derivatives. The work brought to the identification of compound 28, a 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivative, with potent 5-HT2A antagonism, >100 fold selectivity over other serotonin subtype receptors and high affinity for the α1 receptor. Moreover, when administered locally, 28 showed superior ocular hypotensive action in vivo, compared to the clinically used reference compound timolol.