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

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. H...

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Published inJournal of medicinal chemistry Vol. 66; no. 1; pp. 413 - 434
Main Authors Kim, Bo Yi, Oh, Changmok, Jeon, Dongkyu, Jun, Ikhyun, Lee, Ho K., Kim, Bo-Rahm, Park, Jinhong, Seo, Kyoung Yul, Kim, Kyeong-A, Lim, Dami, Lee, Seolhee, Lee, Jooyun, Yoon, Hongchul, Kim, Tae-im, Namkung, Wan
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 12.01.2023
Amer Chemical Soc
Subjects
Animals
Chemistry, Medicinal
Conjunctiva - metabolism
Cornea
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Dry Eye Syndromes - drug therapy
Dry Eye Syndromes - genetics
Dry Eye Syndromes - metabolism
Life Sciences & Biomedicine
Mice
Pharmacology & Pharmacy
Pyrimidines - metabolism
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
Rabbits
Science & Technology
Solubility
Tears - metabolism
CORNEAL
SJOGRENS
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Summary: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.
Bibliography:ObjectType-Article-1
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c01382