Gaucher disease, resulting from deficient lysosomal glucocerebrosidase (GC) activity, is the most common lysosomal storage disorder. Clinically important GC mutant enzymes typically have reduced specific activity and reduced lysosomal concentration, the latter due to compromised folding and trafficking. We and others have demonstrated that pharmacological chaperones assist variant GC folding by binding to the active site, stabilizing the native conformation of GC in the neutral pH environment of the endoplasmic reticulum (ER), enabling its trafficking from the ER to the Golgi and on to the lysosome. The mutated GC fold is generally stable in the lysosome after pharmacological chaperone dissociation, owing to the low pH environment for which the fold was evolutionarily optimized and the high substrate concentration, enabling GC to hydrolyze glucosylceramide to glucose and ceramide. The hypothesis of this study was that we could combine GC pharmacological chaperone structure-activity relationships from distinct chemical series to afford potent novel chaperones comprising a carbohydrate-like substructure that binds in the active site with a hydrophobic substructure that binds in a nearby pocket. We combined isofagomine and 2,5-anhydro-2,5-imino-D-glucitol active site binding substructures with hydrophobic alkyl adamantyl amides to afford novel small molecules with enhanced ability to increase GC activity in patient-derived fibroblasts. The cellular activity of N370S and G202R GC in fibroblasts is increased by 2.5- and 7.2-fold with isofagmine-based pharmacological chaperones N-adamantanyl-4-((3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)piperidin-1-yl)-butanamide (3) and N-adamantanyl-4-((3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)piperidin-1-yl)pentanamide (4), respectively, the best enhancements observed to date.