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Several carba analogues comprising a 13- or 14-membered heterocycle were synthesized and assessed ( 28 exhibited a Ki value of 4.1 nM and the corresponding analogue with a saturated double bond, compound 29 , a Ki value of 25 nM, demonstrating that a proper constrain of flexibility of the ring system, alternatively an electron density in the center of the lipophilic bridge between amino acid residues in positions 1 and 3 is favorable for affinity to IRAP (Figure 7)

Early research deserves attention, but context matters just as much as the findings themselves