TRPA1抑制剂通过抑制哮喘治疗中的神经源性炎症和气道收缩治疗哮喘
2021/03/22
摘要
尽管开发出了有效的疗法，但是很大一部分的哮喘患者仍然具有不受控制的症状，气流受限和急性加重。 瞬时受体电位阳离子通道成员A1（TRPA1）激动剂在人的哮喘气道中升高；在啮齿动物中，TRPA1参与气道炎症和诱导反气道高反应性。在此，我们描述了GDC-0334（一种高效，选择性和具有口服生物利用度TRPA1拮抗剂）的发现和早期临床开发。 GDC-0334在一些临床前物种中抑制TRPA1对气道平滑肌和感觉神经元的功能，减少水肿，皮肤血流量（DBF），咳嗽和过敏性气道炎症。在一项健康者自愿的1期研究中，GDC-0334的治疗减少了TRPA1激动剂诱导的DBF，疼痛和瘙痒，证明了GDC-0334在人类中的靶向参与。这些数据为评估TRPA1抑制剂作为哮喘的临床治疗方法提供了治疗依据。
A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment
Alessia Balestrini, Victory Joseph, Michelle Dourado, Rebecca M Reese, Shannon D Shields, Lionel Rougé , Daniel D Bravo, Tania Chernov-Rogan, Cary D Austin, Huifen Chen , Lan Wang, Elisia Villemure, Daniel G M Shore, Vishal A Verma, Baihua Hu, Yong Chen, Laurie Leong, Chris Bjornson, Kathy Hötzel , Alvin Gogineni, Wyne P Lee, Eric Suto, Xiumin Wu, John Liu, Juan Zhang, Vineela Gandham, Jianyong Wang, Jian Payandeh, Claudio Ciferri, Alberto Estevez, Christopher P Arthur , Jens Kortmann, Ryan L Wong, Jose E Heredia, Jonas Doerr, Min Jung, Jason A Vander Heiden , Merone Roose-Girma , Lucinda Tam, Kai H Barck , Richard A D Carano, Han Ting Ding, Bobby Brillantes, Christine Tam, Xiaoying Yang, Simon S Gao, Justin Q Ly, Liling Liu, Liuxi Chen, Bianca M Liederer, Joseph H Lin, Steven Magnuson, Jun Chen , David H Hackos, Justin Elstrott , Alexis Rohou, Brian S Safina, Matthew Volgraf, Rebecca N Bauer, Lorena Riol-Blanco
Abstract
Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
尽管开发出了有效的疗法，但是很大一部分的哮喘患者仍然具有不受控制的症状，气流受限和急性加重。 瞬时受体电位阳离子通道成员A1（TRPA1）激动剂在人的哮喘气道中升高；在啮齿动物中，TRPA1参与气道炎症和诱导反气道高反应性。在此，我们描述了GDC-0334（一种高效，选择性和具有口服生物利用度TRPA1拮抗剂）的发现和早期临床开发。 GDC-0334在一些临床前物种中抑制TRPA1对气道平滑肌和感觉神经元的功能，减少水肿，皮肤血流量（DBF），咳嗽和过敏性气道炎症。在一项健康者自愿的1期研究中，GDC-0334的治疗减少了TRPA1激动剂诱导的DBF，疼痛和瘙痒，证明了GDC-0334在人类中的靶向参与。这些数据为评估TRPA1抑制剂作为哮喘的临床治疗方法提供了治疗依据。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(J Exp Med . 2021 Apr 5;218(4):e20201637. doi: 10.1084/jem.20201637.)
(J Exp Med . 2021 Apr 5;218(4):e20201637. doi: 10.1084/jem.20201637.)
A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment
Alessia Balestrini, Victory Joseph, Michelle Dourado, Rebecca M Reese, Shannon D Shields, Lionel Rougé , Daniel D Bravo, Tania Chernov-Rogan, Cary D Austin, Huifen Chen , Lan Wang, Elisia Villemure, Daniel G M Shore, Vishal A Verma, Baihua Hu, Yong Chen, Laurie Leong, Chris Bjornson, Kathy Hötzel , Alvin Gogineni, Wyne P Lee, Eric Suto, Xiumin Wu, John Liu, Juan Zhang, Vineela Gandham, Jianyong Wang, Jian Payandeh, Claudio Ciferri, Alberto Estevez, Christopher P Arthur , Jens Kortmann, Ryan L Wong, Jose E Heredia, Jonas Doerr, Min Jung, Jason A Vander Heiden , Merone Roose-Girma , Lucinda Tam, Kai H Barck , Richard A D Carano, Han Ting Ding, Bobby Brillantes, Christine Tam, Xiaoying Yang, Simon S Gao, Justin Q Ly, Liling Liu, Liuxi Chen, Bianca M Liederer, Joseph H Lin, Steven Magnuson, Jun Chen , David H Hackos, Justin Elstrott , Alexis Rohou, Brian S Safina, Matthew Volgraf, Rebecca N Bauer, Lorena Riol-Blanco
Abstract
Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
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