Late-stage optimization of a tercyclic class of S1P₃-sparing, S1P₁ receptor agonists

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• 作者：Joshua C. Horan^a ; ^{joshua.horan@proteostasis.com" class="auth_mail" title="E-mail the corresponding author} ; Daniel Kuzmich^a ; Pingrong Liu^a ; Darren DiSalvo^a ; John Lord^a ; Can Mao^a ; Tamara D. Hopkins^a ; Hui Yu^a ; Christian Harcken^a ; Raj Betageri^a ; Melissa Hill-Drzewi^a ; Lori Patenaude^b ; Monica Patel^a ; Kimberly Fletcher^a ; Donna Terenzzio^a ; Brian Linehan^a ; Heather Xia^a ; Mita Patel^a ; Debbie Studwell^c ; Craig Miller^a ; Eugene Hickey^a ; Jeremy I. Levin^a ; Dustin Smith^a ; Raymond A. Kemper^c ; Louise K. Modis^b ; Lynne C. Bannen^d ; Diva S. Chan^d ; Morrison B. Mac^d ; Stephanie Ng^d ; Yong Wang^d ; Wei Xu^d ; René ; M. Lemieux^a
• 关键词：SFBFJQXHRYGKHV-INIZCTEOSA-N ; SDCQNJRPSLMFIT-SFHVURJKSA-N ; GMEODUAZQQLOFF-MRXNPFEDSA-N ; MUINZQQLLPFAQS-OAHLLOKOSA-N
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：26
• 期：2
• 页码：466-471
• 全文大小：1129 K

文摘

Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.