Figure 2 | Scientific Reports

Figure 2

From: Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor

Figure 2

Identification of a novel potent and brain penetrant CGT inhibitor. S221 was identified in a screen of a focused bioactive lipid library (A). S221 was determined to be an oxidation product of (CAY10508), which had acquired a hydroxyl group (in red) on the central ring. Through a medicinal chemistry effort S202 was discovered as a more potent CGT inhibitor (B) showing a 400-fold increased potency in a CGT enzyme assay (C) and single digit nanomolar potency in a CGT cellular assay (D) (n = 2 per concentration). Mouse pharmacokinetic (PK) and brain concentration profile graph (n = 3, E) and PK parameter table (F) for S202 after a single IP injection show favorable in vivo half-life and brain penetration properties.

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