Optimization of a Macrocyclic Ghrelin Receptor Agonist (Part II)

The initial lead optimization efforts on the foregoing macrocyclic ghrelin agonists from the high-throughput screening (HTS) hit, from a diverse library of macrocyclic peptidomimetics encompassing a tripeptide connected head to tail by a non-peptidic tether, to the initial clinical candidate, in terms of potency and pharmacokinetic (PK) properties, were reported previously. This chapter presents a summary of the efforts that culminated in the nomination of TZP-102 as the second clinical candidate from the ghrelin agonist program. Improving CYP 3A4 off-target profile in ulimorelin was one of the key goals in the second round of advanced lead optimization. In the lead optimization beyond ulimorelin that culminated in the discovery of TZP-102, the key features of CYP 3A4 were generally retained, and the main focus was directed to additional optimization through the AA3 side chain (more tolerant in terms of bioactivity structure-activity relationship (SAR)), as well as the less explored tether regions in the lead structure.