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Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-06-28 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00521 James Reuberson 1 , Helen Horsley 1 , Richard J. Franklin 1 , Daniel Ford 1 , Judi Neuss 1 , Daniel Brookings 1 , Qiuya Huang 2 , Bart Vanderhoydonck 2 , Ling-Jie Gao 2 , Mi-Yeon Jang 2 , Piet Herdewijn 2 , Anant Ghawalkar 3 , Farnaz Fallah-Arani 1 , Adnan R. Khan 1 , Jamie Henshall 1 , Mark Jairaj 1 , Sarah Malcolm 1 , Eleanor Ward 1 , Lindsay Shuttleworth 1 , Yuan Lin 2 , Shengqiao Li 2 , Thierry Louat 2 , Mark Waer 2 , Jean Herman 2 , Andrew Payne 1 , Tom Ceska 1 , Carl Doyle 1 , Will Pitt 1 , Mark Calmiano 1 , Martin Augustin 4 , Stefan Steinbacher 4 , Alfred Lammens 4 , Rodger Allen 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-06-28 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00521 James Reuberson 1 , Helen Horsley 1 , Richard J. Franklin 1 , Daniel Ford 1 , Judi Neuss 1 , Daniel Brookings 1 , Qiuya Huang 2 , Bart Vanderhoydonck 2 , Ling-Jie Gao 2 , Mi-Yeon Jang 2 , Piet Herdewijn 2 , Anant Ghawalkar 3 , Farnaz Fallah-Arani 1 , Adnan R. Khan 1 , Jamie Henshall 1 , Mark Jairaj 1 , Sarah Malcolm 1 , Eleanor Ward 1 , Lindsay Shuttleworth 1 , Yuan Lin 2 , Shengqiao Li 2 , Thierry Louat 2 , Mark Waer 2 , Jean Herman 2 , Andrew Payne 1 , Tom Ceska 1 , Carl Doyle 1 , Will Pitt 1 , Mark Calmiano 1 , Martin Augustin 4 , Stefan Steinbacher 4 , Alfred Lammens 4 , Rodger Allen 1
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The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4-d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.
中文翻译：
发现一种有效的，口服生物利用的PI4KIIIβ抑制剂（UCB9608），能够显着延长体内的同种异体器官植入
一系列新型的免疫抑制7-哌嗪-1-基噻唑并[5,4 - d ]嘧啶-5-胺类化合物的主要目标被确定为脂质激酶PI4KIIIβ。该系列的评价突出了它们的溶解性差和不需要的脱靶活性。采取了一种药物化学策略，以优化该系列中的理化特性，同时保持了效力，并提高了与其他脂质激酶相比的选择性。化合物22最初在体内被鉴定和鉴定，然后进一步修饰导致发现44（UCB9608），这是一种具有更高的代谢稳定性和出色的药代动力学特征的溶解度更高的选择性化合物。共晶体结构为44解决了与PI4KIIIβ的结合，证实了这类抑制剂的结合方式。体内44处大大改善的位置使其成为理想的工具化合物，可进一步建立PI4KIIIβ抑制与延长的同种异体器官移植以及体内免疫反应抑制之间的联系。
更新日期：2018-06-28
中文翻译：
发现一种有效的，口服生物利用的PI4KIIIβ抑制剂（UCB9608），能够显着延长体内的同种异体器官植入
一系列新型的免疫抑制7-哌嗪-1-基噻唑并[5,4 - d ]嘧啶-5-胺类化合物的主要目标被确定为脂质激酶PI4KIIIβ。该系列的评价突出了它们的溶解性差和不需要的脱靶活性。采取了一种药物化学策略，以优化该系列中的理化特性，同时保持了效力，并提高了与其他脂质激酶相比的选择性。化合物22最初在体内被鉴定和鉴定，然后进一步修饰导致发现44（UCB9608），这是一种具有更高的代谢稳定性和出色的药代动力学特征的溶解度更高的选择性化合物。共晶体结构为44解决了与PI4KIIIβ的结合，证实了这类抑制剂的结合方式。体内44处大大改善的位置使其成为理想的工具化合物，可进一步建立PI4KIIIβ抑制与延长的同种异体器官移植以及体内免疫反应抑制之间的联系。
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