SAR of a series of related peptidomimetics derived from a novel hematoregulatory peptide, SK&F 107647

We have previously reported the hematopoietic activity of a novel peptide, SK&F 107647 (1)[1]. This peptide has been shown to induce from stromal cells a novel factor, designated hematopoietic synergistic factor (HSF), which directly enhances host effector cell function and synergizes endogenous growth factors, such as G-, Mand GM-CSF [2, 3]. An examination of the SAR of 1 allowed the formulation of a pharmacophore model in which the Asp and Lys residues of 1 interact with each other by forming either interor intrachain salt bridges about the linking 2-(S),7-(S)-diaminosuberic acid (Sub) residue [1, 4]. This combination of the salt bridges and the Sub residue act as a scaffold which presents the residues, and in the correct orientation [4]. These residues are responsible for the putative receptor interaction. As an initial validation of this hypothesis, this saltbridge containing scaffold has been replaced by a much simpler structural template to give the peptidomimetic analog 2 which displayed significant hematopoietic activity [4].