Abstract
A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined. Compounds 15 and 27 stood out as leads due to their good cellular as well as human whole blood IDO1 inhibition activity, low unbound clearance, and reasonable mean residence time in rat cassette PK studies.
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MeSH terms
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Animals
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Catalytic Domain
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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HeLa Cells
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Humans
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Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
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Indoleamine-Pyrrole 2,3,-Dioxygenase / chemistry
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Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
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Molecular Docking Simulation
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Naphthyridines / chemical synthesis
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Naphthyridines / metabolism
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Naphthyridines / pharmacokinetics
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Naphthyridines / pharmacology*
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Pyrroles / chemical synthesis
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Pyrroles / metabolism
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology*
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Quinolines / chemical synthesis
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Quinolines / metabolism
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Quinolines / pharmacokinetics
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Quinolines / pharmacology*
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Rats
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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IDO1 protein, human
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Naphthyridines
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Pyrroles
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Quinolines