Synthetic Strategies for Improving Solubility: Optimization of Novel Pyrazolo[1,5- a]pyrimidine CFTR Activator That Ameliorates Dry Eye Disease

Bo Yi Kim, Changmok Oh, Dongkyu Jeon, Ikhyun Jun, Ho K. Lee, Bo Rahm Kim, Jinhong Park, Kyoung Yul Seo, Kyeong A. Kim, Dami Lim, Seolhee Lee, Jooyun Lee, Hongchul Yoon, Tae Im Kim, Wan Namkung

Research output: Contribution to journalArticlepeer-review

Abstract

Dry eye disease (DED) is one of the most prevalent ocular diseases but has limited treatment options. Cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel that stimulates fluid secretion in the ocular surface, may pave the way for new therapeutic strategies for DED. Herein, we report the optimization of Cact-3, a potent CFTR activator with poor solubility, to 16d, a potent CFTR activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of 16d significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, 16d significantly reduced mRNA expression of pro-inflammatory cytokines including IL-1β, IL-17, and TNF-α and MMP2 in cornea and conjunctiva of DED mice.

Original languageEnglish
JournalJournal of Medicinal Chemistry
DOIs
Publication statusAccepted/In press - 2022

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF-2018R1A6A1A03023718, NRF-2020R1C1C1008332, and NRF-2021R1I1A1A01047951).

Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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