Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors.

•Substituted pyranopyrazoles as novel AKR1C3 inhibitors.•Crystal structure revealed a unique binding pattern.•Pyranopyrazoles change conformations to suit AKR1C3 and AKR1C1.•Meclofenamic acid reshapes itself to fit AKR1C3 and AKR1C1.•Conformational changes of ligand should be considered in design of AKR1C3 inhibitor.