Structural optimization of anti-hypoxic candidates guided by FGF21 and GDF15 mRNA expression

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Current therapeutics for acute mountain sickness (AMS) are limited, with no new drugs developed in over 50 years.
• FGF21 and GDF15 are key regulators of metabolic reprogramming in response to hypoxia.
• H0802, a previously characterized compound, demonstrated anti-hypoxic effects by regulating FGF21 and GDF15 mRNA expression.

Purpose of the Study:

• To explore the structure-activity relationship of H0802 derivatives for developing novel AMS therapeutics.
• To identify new small molecules that enhance hypoxia tolerance by modulating FGF21 and GDF15 expression.

Main Methods:

• Designed and synthesized 28 novel compounds based on the RNA-regulation phenotypes of FGF21 and GDF15.
• Tested compound efficacy on primary liver cells, measuring FGF21 and GDF15 mRNA expression.
• Evaluated promising candidates (YXX0237, YXX0248) in vivo using hypoxia tolerance models and conducted preliminary safety and pharmacokinetic studies.

Main Results:

• YXX0237 and YXX0248 significantly upregulated FGF21 and GDF15 levels both in vitro and in vivo.
• Both compounds enhanced hypoxia tolerance in mice during closed hypoxia experiments.
• Preliminary safety assessments indicated low cytotoxicity and high LD50 values (>500 mg/kg) for YXX0237 and YXX0248.
• YXX0237 demonstrated superior bioavailability and pharmacokinetic profile compared to YXX0248.

Conclusions:

• This study presents a novel drug-discovery strategy targeting FGF21 and GDF15 expression for hypoxia-related diseases.
• Structure-activity relationship analysis provides a basis for optimizing H0802 derivatives.
• YXX0237 emerges as a potential therapeutic candidate for treating hypoxia-related conditions due to its efficacy and favorable safety profile.