Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4‐Dihydropyrazino[1,2‐b]indazol‐1(2H)‐one Derivatives,ChemMedChem

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Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4‐Dihydropyrazino[1,2‐b]indazol‐1(2H)‐one Derivatives
ChemMedChem ( IF 3.6 ) Pub Date : 2018-07-09 , DOI: 10.1002/cmdc.201800199
Guido Furlotti ₁ , Maria Alessandra Alisi ₁ , Nicola Cazzolla ₁ , Francesca Ceccacci _{2,

3} , Beatrice Garrone ₁ , Tecla Gasperi ₄ , Angela La Bella ₂ , Francesca Leonelli _{2,

5} , Maria Antonietta Loreto ₂ , Gabriele Magarò ₁ , Giorgina Mangano ₁ , Rinaldo Marini Bettolo ₂ , Emanuela Masini ₆ , Martina Miceli ₄ , Luisa Maria Migneco ₂ , Marco Vitiello ₁

Affiliation

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.

中文翻译：

针对眼用降压药的血清素2A和肾上腺素α1受体：发现3,4-二氢吡嗪并[1,2-b]吲唑-1（2H）-one衍生物

青光眼影响着全球数百万人，并引起视神经损害和失明。眼内压升高（IOP）是与此病理相关的主要危险因素，而降低IOP是当前药物治疗的关键治疗目标。作为潜在的降眼压剂，我们研究的化合物，即对两个受体（血清素2A和肾上腺素能α行为₁连接到房水动力学的调节）。在本文中，我们描述了一系列新型双环和三环N 2-烷基-吲唑酰胺衍生物的设计，合成和药理作用。这项研究确定了3,4-二氢吡嗪并[1,2 - b ]吲唑-1（2 H）具有强效的血清素2A受体拮抗作用-酮衍生物，>比其他血清素亚型受体100倍的选择性，而对于α高亲和力₁受体。此外，相对于临床使用的参考化合物噻吗洛尔，在局部给药时，该化合物在体内显示出优异的眼降压作用。

更新日期：2018-07-09

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