3 research outputs found
Optimization of Novel Antagonists to the Neurokinin‑3 Receptor for the Treatment of Sex-Hormone Disorders (Part II)
Further lead optimization on <i>N</i>-acyl-triazolopiperazine antagonists to the neurokinin-3
receptor (NK<sub>3</sub>R) based on the concurrent improvement in
bioactivity and ligand lipophilic efficiency (LLE) is reported. Overall,
compound <b>3</b> (LLE > 6) emerged as the most efficacious
in castrated rat and monkey to lower plasma LH, and it displayed the
best off-target safety profile that led to its clinical candidate
nomination for the treatment of sex-hormone disorders
Discovery and Optimization of Novel Antagonists to the Human Neurokinin‑3 Receptor for the Treatment of Sex-Hormone Disorders (Part I)
Neurokinin-3
receptor (NK<sub>3</sub>R) has recently emerged as
important in modulating the tonic pulsatile gonadotropin-releasing
hormone (GnRH) release. We therefore decided to explore NK<sub>3</sub>R antagonists as therapeutics for sex-hormone disorders that can
potentially benefit from lowering GnRH pulsatility with consequent
diminished levels of plasma luteinizing hormone (LH) and correspondingly
attenuated levels of circulating androgens and estrogens. The discovery
and lead optimization of a novel <i>N</i>-acyl-triazolopiperazine
NK<sub>3</sub>R antagonist chemotype achieved through bioisosteric
lead change from the high-throughput screening (HTS) hit is described.
A concomitant improvement in the antagonist bioactivity and ligand
lipophilic efficiency (LLE) parameter were the principal guidelines
in the lead optimization efforts. Examples of advanced lead analogues
to demonstrate the amenability of this chemotype to achieving a suitable
pharmacokinetic (PK) profile are provided as well as pharmacokinetic–pharmacodynamic
(PKPD) correlations to analyze the trends observed for LH inhibition
in castrated rats and monkeys that served as preliminary in vivo efficacy
models
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 Pharma’s
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-I′ β-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