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 (NK₃R) 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 (NK₃R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. We therefore decided to explore NK₃R 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 NK₃R 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 Ca²⁺-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>_i = 86 nM, EC₅₀ = 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>_i = 16 nM, EC₅₀ = 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