Fig. 4: Synthesis route to novel MAGL inhibitors. | Nature Communications

Fig. 4: Synthesis route to novel MAGL inhibitors.

From: Expediting hit-to-lead progression in drug discovery through reaction prediction and multi-dimensional optimization

Fig. 4

A The Minisci-type alkylation approach delivered a shortened synthesis route. Rather than through seven steps (orange, a–g), the left-hand side building blocks (9a-i) were obtained in three steps (blue, h–j). Consequent coupling with different right-hand side building blocks (13–16) delivered 14 MAGL inhibitors (18–31). a H2O, 0 ∘C, 2 eq. KOH, 10% F2 in N2; b neat, 120 ∘C, 1.4 eq. PBr5; c EtOH, rt, 1.0 eq. NaBH4; d Toluene/H2O 10:1, 100 ∘C, 1.26 eq. R-boronic acid, 0.3 eq. PCy3, 0.1 eq. Pd2(dba)3*CHCl3, 3.0 eq. K2CO3; e HCl aq., 80 ∘C; f THF, rt, 1.3 eq. CDI, 1.3 eq. 7; g polyphosphoric acid, 120 ∘C; h THF, rt, 1.3 eq. CDI, 1.3 eq.; i polyphosphoric acid, 120 ∘C; j MeCN/H2O 3:2, 80 ∘C, 3.0 eq. 12, 3.0 eq. (NH4)2S2O8, 0.1 eq. AgSCF3; k a. MeOH, rt, 5.0 eq. LiOH b. DMF, rt, 1.2 eq. 13/14/15/16, 10.0 eq. DIPEA, 1.1 eq. HATU; B Crystal structure complexes of human monoacylglycerol lipase (MAGL) with hit compound 17, and inhibitors 23, 27, and 29, shown in pale, light green, light blue, and royal blue, respectively. From left to right, a close-up view of the binding poses of 23, 27, and 29, along with some of their key interactions (i.e., hydrogen bonds to Met123, Ala51, Arg57, and two crystal water molecules, and π-stacking with Tyr194) is shown. Additionally, an overlay of the three inhibitors (23, 27, and 29) with the hit structure 17 is depicted. Source data are provided in a Source Data file. Abbreviations: cPen: Cyclopentyl (A37), cHex: Cyclohexyl (A36), cPr-cBu: Cyclopropyl-cyclobutyl (A31), Pip: Piperidine (A25).

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