Discovery of a New Class of Macrocyclic Antagonists to the Human Motilin Receptor

Abstract

A novel class of macrocyclic peptidomimetics was identified and optimized as potent antagonists to the human motilin receptor (hMOT-R). Well-defined structure-activity relationships allowed for rapid optimization of potency that eventually led to high affinity antagonists to hMOT-R. Potency and antagonist functional activity were confirmed both in functional and cell-based assays, as well as on isolated rabbit intestinal smooth muscle strips. Rapid access to this novel class of macrocyclic target structures was made possible through two efficient and complementary solid-phase parallel synthetic approaches, both of which are reported herein.

Ghrelin receptor modulators: a patent review (2011 – 2014)

“…The general structure of the Tranzyme Pharma macrocycles is represented in Figure 1. The Tranzyme Pharma's proprietary library has also generated macrocyclic antagonists of the same general formula as human motilin antagonists for the treatment of gastrointestinal (GI) disorders associated with impaired gut mobility [65]. Motilin is a 22-aminoacid peptide released from the gut that plays an important role in the regulation of intestinal motility.…”

Macrocycles

“…Macrocycles are often seen as too complex for parallel production of libraries. Solid phase synthesis was, for instance, used to produce .10,000 cpd libraries [18]. Thus, the pharmaceutical industry should undertake the necessary effort to bring this additional structural diversity into their compound collections.…”

The Synthesis of Macrocycles for Drug Discovery

“…356 Screening of these libraries led to the discovery of highly active and selective ghrelin agonists (ulimorelin, 268) 349 and motilin antagonists (270, Figure 11.19). 357,358 For solution phase approaches as well, macrolactamization has often been the method of choice for the key step in the synthesis of macrocyclic libraries, in part because of its high efficiency and wide reagent selection. For example, research on construction of a library of smaller cyclic peptidomimetics led to optimized conditions for an intramolecular lactamization (HATU, DMF-CH 3 CN, slow addition) to create the triply orthogonal protected template 271 (Figure 11.19, site of cyclization and reagent employed indicated), 359 which could then be further diversified using a variety of standard transformations.…”