Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases

被引：42

作者：

Hemmerling, Martin ^{[1
]}

Nilsson, Stinabritt ^{[5
]}

Edman, Karl ^{[2
]}

Eirefelt, Stefan ^{[5
]}

Russell, Wayne ^{[5
]}

Hendrickx, Ramon ^{[1
]}

Johnsson, Eskil ^{[1
]}

Mardh, Carina Karrman ^{[1
]}

Berger, Markus ^{[4
]}

Rehwinkel, Hartmut ^{[4
]}

Abrahamsson, Anna ^{[1
]}

Dahmen, Jan ^{[5
]}

Eriksson, Anders R. ^{[1
]}

Gabos, Balint ^{[5
]}

Henriksson, Krister ^{[5
]}

Hossain, Nafizal ^{[5
]}

Ivanova, Svetlana ^{[5
]}

Jansson, Anne-Helene ^{[5
]}

Jensen, Tina J. ^{[1
]}

Jerre, Anders ^{[5
]}

Johansson, Henrik ^{[5
]}

Klingstedt, Tomas ^{[5
]}

Lepisto, Matti ^{[1
]}

Lindsjo, Martin ^{[3
]}

Mile, Irene ^{[5
]}

Nikitidis, Grigorios ^{[5
]}

Steele, John ^{[1
]}

Tehler, Ulrika ^{[3
]}

Wissler, Lisa ^{[2
]}

Hanson, Thomas ^{[1
]}

机构：

[1] AstraZeneca, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun, Pepparedsleden 1, SE-43183 Molndal, Sweden

[2] AstraZeneca, Innovat Med & Early Dev Biotech Unit, Discovery Sci, Pepparedsleden 1, SE-43183 Molndal, Sweden

[3] AstraZeneca, Innovat Med & Early Dev Biotech Unit, Pharmaceut Sci, Pepparedsleden 1, SE-43183 Molndal, Sweden

[4] Bayer AG, Pharmaceut, Drug Discovery, Med Chem Berlin, D-13353 Berlin, Germany

[5] AstraZeneca R&D, Scheelevagen 1, SE-22187 Lund, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 20期

关键词：

FLUTICASONE FUROATE; IN-VITRO; CORTICOSTEROIDS; DISCOVERY; BINDING; POTENT; PHARMACOKINETICS; CICLESONIDE; BUDESONIDE; DESIGN;

D O I：

10.1021/acs.jmedchem.7b01215

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate lb (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

引用

页码：8591 / 8605

页数：15

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