Biomedical Engineering Reference
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SCHEME 8.10 Solid-phase synthesis of a library of tethered 14- to 22-membered semipep-
tidic macrocycles using a semilabile thioester linker for cyclative cleavage as the macrocy-
clization reaction.
release ( 54 ), were also developed [75]. Using this technology, the authors produced
a library of about 20,000 macrocycles with broad diversity in terms of side chains,
stereochemistry, and types of amino acids, ring size, and the chemical nature of the
tether [19]. This collection of macrocycles delivered nanomolar-level hits on several
peptidergic G-protein-coupled receptors directly from HTS, which constituted an
enviable starting point for multiple drug discovery programs.
Agonists of the ghrelin receptor identified via this technology are now in advanced
clinical development, as exemplified by ulimorelin (TZP-101, 55 , Figure 8.6) [76],
which was developed as an i.v. candidate for the treatment of postoperative ileus [77].
Although administered i.v. for this particular indication, the compound possesses
24% oral bioavailability with a low clearance (8.8 mL/min/kg) [76a]. A thorough
analysis of structure-activity and structure-pharmacokinetic relationships disclosed
the critical role of specific amino acids of the tripeptide portion and the nonpeptidic
tether, revealing a subtle interplay between different parts of the molecule in the
control of its pharmacodynamic and pharmacokinetic profiles. A second-generation
ghrelin agonist (TZP-102) is currently in clinical phase II as an oral candidate for
the treatment of diabetic gastroparesis [72a]. As a remarkable example of efficacy
switch, this scaffold also delivered a novel series of antagonists of the ghrelin receptor
exemplified by 56 , demonstrating how minute modifications of exocyclic substituents
can affect biological activity dramatically [1c]. The same library also led to the
discovery of potent and selective motilin antagonists exemplified by 57 [75,78].
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