TY - JOUR
T1 - Synthetic Strategies for Improving Solubility
T2 - Optimization of Novel Pyrazolo[1,5- a]pyrimidine CFTR Activator That Ameliorates Dry Eye Disease
AU - Kim, Bo Yi
AU - Oh, Changmok
AU - Jeon, Dongkyu
AU - Jun, Ikhyun
AU - Lee, Ho K.
AU - Kim, Bo Rahm
AU - Park, Jinhong
AU - Seo, Kyoung Yul
AU - Kim, Kyeong A.
AU - Lim, Dami
AU - Lee, Seolhee
AU - Lee, Jooyun
AU - Yoon, Hongchul
AU - Kim, Tae Im
AU - Namkung, Wan
N1 - 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.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.2c01382
DO - 10.1021/acs.jmedchem.2c01382
M3 - Article
C2 - 36573286
AN - SCOPUS:85145314935
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
ER -