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Discovery of Potent and Orally Bioavailable Small Molecule Antagonists of Toll-like Receptors 7/8/9 (TLR7/8/9).
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-07-29 , DOI: 10.1021/acsmedchemlett.0c00264 Christopher P Mussari 1 , Dharmpal S Dodd 1 , Ratna Kumar Sreekantha 2 , Laxman Pasunoori 2 , Honghe Wan 1 , Shana L Posy 1 , David Critton 1 , Stefan Ruepp 1 , Murali Subramanian 2 , Andrew Watson 1 , Paul Davies 1 , Gary L Schieven 1 , Luisa M Salter-Cid 1 , Ratika Srivastava 2 , Debarati Mazumder Tagore 2 , Shailesh Dudhgaonkar 2 , Michael A Poss 1 , Percy H Carter 1 , Alaric J Dyckman 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-07-29 , DOI: 10.1021/acsmedchemlett.0c00264 Christopher P Mussari 1 , Dharmpal S Dodd 1 , Ratna Kumar Sreekantha 2 , Laxman Pasunoori 2 , Honghe Wan 1 , Shana L Posy 1 , David Critton 1 , Stefan Ruepp 1 , Murali Subramanian 2 , Andrew Watson 1 , Paul Davies 1 , Gary L Schieven 1 , Luisa M Salter-Cid 1 , Ratika Srivastava 2 , Debarati Mazumder Tagore 2 , Shailesh Dudhgaonkar 2 , Michael A Poss 1 , Percy H Carter 1 , Alaric J Dyckman 1
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The toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system, responsible for the early detection of foreign or endogenous threat signals. In the context of autoimmunity, the unintended recognition of self-motifs as foreign promotes initiation or propagation of disease. Overactivation of TLR7 and TLR9 have been implicated as factors contributing to autoimmune disorders such as psoriasis, arthritis, and lupus. In our search for small molecule antagonists of TLR7/9, 7f was identified as possessing excellent on-target potency for human TLR7/9 as well as for TLR8, with selectivity against other representative TLR family members. Good pharmacokinetic properties and a relatively balanced potency against TLR7 and TLR9 in mouse systems (systems which lack functional TLR8) made this an excellent in vivo tool compound, and efficacy from oral dosing in preclinical models of autoimmune disease was demonstrated.
中文翻译：
Toll 样受体 7/8/9 (TLR7/8/9) 的强效口服生物可利用小分子拮抗剂的发现。
Toll 样受体 (TLR) 家族是先天免疫系统进化上保守的组成部分，负责早期检测外来或内源性威胁信号。在自身免疫的背景下，无意中将自身基序识别为外来的会促进疾病的发生或传播。TLR7 和 TLR9 的过度激活被认为是导致自身免疫性疾病（如银屑病、关节炎和狼疮）的因素。在我们的TLR7 / 9，小分子拮抗剂搜索1408米被鉴定为对人 TLR7/9 和 TLR8 具有出色的靶向效力，对其他代表性 TLR 家族成员具有选择性。在小鼠系统（缺乏功能性 TLR8 的系统）中，良好的药代动力学特性和相对平衡的 TLR7 和 TLR9 效力使其成为一种出色的体内工具化合物，并且在自身免疫性疾病的临床前模型中证明了口服给药的功效。
更新日期：2020-09-10
中文翻译：
Toll 样受体 7/8/9 (TLR7/8/9) 的强效口服生物可利用小分子拮抗剂的发现。
Toll 样受体 (TLR) 家族是先天免疫系统进化上保守的组成部分，负责早期检测外来或内源性威胁信号。在自身免疫的背景下，无意中将自身基序识别为外来的会促进疾病的发生或传播。TLR7 和 TLR9 的过度激活被认为是导致自身免疫性疾病（如银屑病、关节炎和狼疮）的因素。在我们的TLR7 / 9，小分子拮抗剂搜索1408米被鉴定为对人 TLR7/9 和 TLR8 具有出色的靶向效力，对其他代表性 TLR 家族成员具有选择性。在小鼠系统（缺乏功能性 TLR8 的系统）中，良好的药代动力学特性和相对平衡的 TLR7 和 TLR9 效力使其成为一种出色的体内工具化合物，并且在自身免疫性疾病的临床前模型中证明了口服给药的功效。
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