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Discovery of TP0628103: A Highly Potent and Selective MMP-7 Inhibitor with Reduced OATP-Mediated Clearance Designed by Shifting Isoelectric Points
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-01-12 , DOI: 10.1021/acs.jmedchem.3c01967
Yusuke Oka 1 , Kumi Abe-Sato 1 , Hideaki Tabuse 1 , Yoshifumi Yasukawa 1 , Tohru Yahara 2 , Tomohiro Nishimoto 2 , Masafumi Kamitani 3 , Takuya Fukunaga 3 , Nagahiro Ochiai 3 , Tomoko Kumasaka-Abe 3 , Kosuke Hitaka 4 , Emi Gunji 4 , Hiroki Ohara 4 , Takuya Takeda 4 , Naoki Kojima 4 , Taiji Asami 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-01-12 , DOI: 10.1021/acs.jmedchem.3c01967
Yusuke Oka 1 , Kumi Abe-Sato 1 , Hideaki Tabuse 1 , Yoshifumi Yasukawa 1 , Tohru Yahara 2 , Tomohiro Nishimoto 2 , Masafumi Kamitani 3 , Takuya Fukunaga 3 , Nagahiro Ochiai 3 , Tomoko Kumasaka-Abe 3 , Kosuke Hitaka 4 , Emi Gunji 4 , Hiroki Ohara 4 , Takuya Takeda 4 , Naoki Kojima 4 , Taiji Asami 1
Affiliation
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Matrix metalloproteinase-7 (MMP-7) has been shown to play an important role in pathophysiological processes such as cancer and fibrosis. We previously discovered selective MMP-7 inhibitors by molecular hybridization and structure-based drug design. However, the systemic clearance (CLtot) of the biologically active lead compound was very high. Because our studies revealed that hepatic uptake by organic anion transporting polypeptide (OATP) was responsible for the high CLtot, we found a novel approach to reducing their uptake based on isoelectric point (IP) values as an indicator for substrate recognition by OATP1B1/1B3. Our “IP shift strategy” to adjust the IP values culminated in the discovery of TP0628103 (18), which is characterized by reduced in vitro OATP-mediated hepatic uptake and in vivo CLtot. Our in vitro–in vivo extrapolation of OATP-mediated clearance and the “IP shift strategy” provide crucial insights for a new medicinal chemistry approach to reducing the systemic clearance of OATP1B1/1B3 substrates.
中文翻译：
TP0628103 的发现：一种高效、选择性的 MMP-7 抑制剂，通过移动等电点设计，可减少 OATP 介导的清除
基质金属蛋白酶-7 (MMP-7) 已被证明在癌症和纤维化等病理生理过程中发挥重要作用。我们之前通过分子杂交和基于结构的药物设计发现了选择性 MMP-7 抑制剂。然而，生物活性先导化合物的全身清除率（CL tot ）非常高。因为我们的研究表明有机阴离子转运多肽 (OATP) 的肝脏摄取是导致高 CL tot 的原因，所以我们发现了一种基于等电点 (IP) 值来减少其摄取的新方法，作为 OATP1B1/1B3 底物识别的指标。我们调整 IP 值的“IP 转移策略”最终发现了 TP0628103 ( 18 )，其特点是体外OATP 介导的肝脏摄取和体内CL tot减少。我们对 OATP 介导的清除的体外-体内外推和“IP 转移策略”为减少 OATP1B1/1B3 底物的系统清除的新药物化学方法提供了重要的见解。
更新日期：2024-01-12
中文翻译：
TP0628103 的发现：一种高效、选择性的 MMP-7 抑制剂，通过移动等电点设计，可减少 OATP 介导的清除
基质金属蛋白酶-7 (MMP-7) 已被证明在癌症和纤维化等病理生理过程中发挥重要作用。我们之前通过分子杂交和基于结构的药物设计发现了选择性 MMP-7 抑制剂。然而，生物活性先导化合物的全身清除率（CL tot ）非常高。因为我们的研究表明有机阴离子转运多肽 (OATP) 的肝脏摄取是导致高 CL tot 的原因，所以我们发现了一种基于等电点 (IP) 值来减少其摄取的新方法，作为 OATP1B1/1B3 底物识别的指标。我们调整 IP 值的“IP 转移策略”最终发现了 TP0628103 ( 18 )，其特点是体外OATP 介导的肝脏摄取和体内CL tot减少。我们对 OATP 介导的清除的体外-体内外推和“IP 转移策略”为减少 OATP1B1/1B3 底物的系统清除的新药物化学方法提供了重要的见解。
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