ABSTRACT
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.
Subject(s)
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 RelationshipABSTRACT
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.
Subject(s)
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 RelationshipABSTRACT
Novel, potent small molecule motilin receptor antagonists are described. These peptidomimetic macrocycles are composed of a tripeptide cyclized backbone-to-backbone with a nonpeptidic tether and bear new unnatural amino acids containing basic side chains.
Subject(s)
Amino Acids/chemistry , Macrocyclic Compounds/pharmacology , Receptors, Gastrointestinal Hormone/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Cyclization , Receptors, Gastrointestinal Hormone/chemistry , Receptors, Neuropeptide/chemistryABSTRACT
A novel class of macrocyclic peptidomimetics was identified and optimized as potent antagonists to the human motilin receptor (hMOT-R). Well-defined structure-activity relationships allowed for rapid optimization of potency that eventually led to high affinity antagonists to hMOT-R. Potency and antagonist functional activity were confirmed both in functional and cell-based assays, as well as on isolated rabbit intestinal smooth muscle strips. Rapid access to this novel class of macrocyclic target structures was made possible through two efficient and complementary solid-phase parallel synthetic approaches, both of which are reported herein.
