Abstract
Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Administration, Oral
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Animals
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Anti-Inflammatory Agents / administration & dosage*
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / metabolism*
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Biphenyl Compounds / administration & dosage
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / metabolism
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Caco-2 Cells
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Dose-Response Relationship, Drug
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Drug Discovery / methods*
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Fatty Acid-Binding Proteins / antagonists & inhibitors*
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Fatty Acid-Binding Proteins / metabolism*
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Humans
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Inflammation / drug therapy
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Inflammation / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred ICR
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Protein Binding / drug effects
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Protein Binding / physiology
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Pyrazoles / administration & dosage
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Pyrazoles / chemistry
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Pyrazoles / metabolism
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Treatment Outcome
Substances
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2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid
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Anti-Inflammatory Agents
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Biphenyl Compounds
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FABP4 protein, human
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Fatty Acid-Binding Proteins
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Pyrazoles