Abstract
High-throughput screening of Tranzyme Phar-ma's proprietary macrocycle library using the aequorin Ca 2+-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 1 (K i = 86 nM, EC 50 = 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 2 (K i = 16 nM, EC 50 = 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 2 that is best defined as a nonideal type-I′ β-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN. (Figure presented)
Original language | English (US) |
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Pages (from-to) | 8305-8320 |
Number of pages | 16 |
Journal | Journal of medicinal chemistry |
Volume | 54 |
Issue number | 24 |
DOIs | |
State | Published - Dec 22 2011 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery