2 research outputs found
Design, Synthesis, and StructureāActivity Relationship Studies of a Potent PACE4 Inhibitor
PACE4 plays an important role in
the progression of prostate cancer
and is an attractive target for the development of novel inhibitor-based
tumor therapies. We previously reported the design and synthesis of
a novel, potent, and relatively selective PACE4 inhibitor known as
a Multi-Leu (ML) peptide. In the present work, we examined the ML
peptide through detailed structureāactivity relationship studies.
A variety of ML-peptide analogues modified at the P8āP5 positions
with leucine isomers (Nle, DLeu, and DNle) or substituted at the P1
position with arginine mimetics were tested for their inhibitory activity,
specificity, stability, and antiproliferative effect. By incorporating d isomers at the P8 position or a decarboxylated arginine mimetic,
we obtained analogues with an improved stability profile and excellent
antiproliferative properties. The DLeu or DNle residue also has improved
specificity toward PACE4, whereas specificity was reduced for a peptide
modified with the arginine mimetic, such as 4-amidinobenzylamide
Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic
High-throughput screening of Tranzyme Pharmaās
proprietary
macrocycle library using the aequorin Ca<sup>2+</sup>-bioluminescence
assay against the human ghrelin receptor (GRLN) led to the discovery
of novel agonists against this G-protein coupled receptor. Early hits
such as <b>1</b> (<i>K</i><sub>i</sub> = 86 nM, EC<sub>50</sub> = 134 nM) though potent in vitro displayed poor pharmacokinetic
properties that required optimization. While such macrocycles are
not fully rule-of-five compliant, principally due to their molecular
weight and clogP, optimization of their pharmacokinetic properties
proved feasible largely through conformational rigidification. Extensive
SAR led to the identification of <b>2</b> (<i>K</i><sub>i</sub> = 16 nM, EC<sub>50</sub> = 29 nM), also known as ulimorelin
or TZP-101, which has progressed to phase III human clinical trials
for the treatment of postoperative ileus. X-ray structure and detailed
NMR studies indicated a rigid peptidomimetic portion in <b>2</b> that is best defined as a nonideal type-Iā² Ī²-turn.
Compound <b>2</b> is 24% orally bioavailable in both rats and
monkeys. Despite its potency, in vitro and in gastric emptying studies, <b>2</b> did not induce growth hormone (GH) release in rats, thus
demarcating the GH versus GI pharmacology of GRLN