RESUMEN
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.
Asunto(s)
Química Farmacéutica/métodos , Péptidos Cíclicos/química , Técnicas Químicas Combinatorias , Dimerización , Dipéptidos , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Imitación Molecular , Estructura Molecular , Péptidos/química , Plata/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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]
Asunto(s)
Alanina/análogos & derivados , Péptidos/síntesis química , Alanina/síntesis química , Alanina/química , Amidas/química , Aminoácidos , Indicadores y Reactivos , Espectrometría de Masas , Metilación , Oxazolidinonas/síntesis química , Oxazolidinonas/química , Péptidos/química , Serina/químicaRESUMEN
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.