RESUMO
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.
Assuntos
Compostos Macrocíclicos/síntese química , Peptidomiméticos/síntese química , Receptores de Grelina/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Hormônio do Crescimento/metabolismo , Humanos , Técnicas In Vitro , Macaca fascicularis , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Microssomos Hepáticos/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Peptidomiméticos/farmacocinética , Peptidomiméticos/farmacologia , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Química Farmacêutica/métodos , Peptídeos Cíclicos/química , Técnicas de Química Combinatória , Dimerização , Dipeptídeos , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Mimetismo Molecular , Estrutura Molecular , Peptídeos/química , Prata/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A convergent synthetic methodology has been developed to access both (2S)- and (2R)-3-fluoroalanine and their corresponding N-methyl analogues, in optically pure form, through a common oxazolidinone intermediate that can be obtained from L- or D-serine. In addition, a procedure for incorporation of these unnatural amino acids in peptide scaffolds is also disclosed herein that minimizes the occurrence of beta-elimination during amide bond formation. [reaction: see text]