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 1 (Ki=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 2 (Ki=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 2 that is best defined as a nonideal type-I' ß-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.
Macrocyclic Compounds/chemical synthesis , Peptidomimetics/chemical synthesis , Receptors, Ghrelin/agonists , Administration, Oral , Animals , Biological Availability , Caco-2 Cells , Cell Membrane Permeability , Crystallography, X-Ray , Growth Hormone/metabolism , Humans , In Vitro Techniques , Macaca fascicularis , Macrocyclic Compounds/pharmacokinetics , Macrocyclic Compounds/pharmacology , Magnetic Resonance Spectroscopy , Male , Microsomes, Liver/metabolism , Oligopeptides/chemical synthesis , Oligopeptides/pharmacokinetics , Oligopeptides/pharmacology , Peptidomimetics/pharmacokinetics , Peptidomimetics/pharmacology , Protein Conformation , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship
A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported.
Chemistry, Pharmaceutical/methods , Peptides, Cyclic/chemistry , Combinatorial Chemistry Techniques , Dimerization , Dipeptides , Models, Chemical , Models, Molecular , Molecular Conformation , Molecular Mimicry , Molecular Structure , Peptides/chemistry , Silver/chemistry , Stereoisomerism , Structure-Activity Relationship
