Fouché Marianne, Schäfer Michael, Blatter Markus, Berghausen Jörg, Desrayaud Sandrine, Roth Hans-Jörg
Global Discovery Chemistry/Macrocycles, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
Global Discovery Chemistry/CADD, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
ChemMedChem. 2016 May 19;11(10):1060-8. doi: 10.1002/cmdc.201600083. Epub 2016 Apr 20.
We previously reported the design of several cyclic decapeptides based on a generic scaffold that achieved favorable oral bioavailability and exposure. With the goal to further investigate the potential of this approach, we describe herein the effect of mono- and difunctionalization of this scaffold. A series of cyclic decapeptides were therefore subjected to a range of in vitro assays and pharmacokinetic (PK) studies to investigate whether the introduction of polar or charged groups could be tolerated by the "engineered" scaffold while maintaining good PK profiles. Whereas the introduction of charged amino acids proved-besides maintaining low clearance-to conceal the inherent PK properties of the scaffold, the introduction of polar amino acids (i.e., threonine and pyridyl alanine) led to several cyclic decapeptides exhibiting excellent PK profiles together with a solubility that was significantly improved relative to that of previously reported cyclic decapeptides.
我们之前报道了基于一种通用骨架设计的几种环十肽，该骨架具有良好的口服生物利用度和暴露量。为了进一步研究这种方法的潜力，我们在此描述了该骨架单官能化和双官能化的效果。因此，一系列环十肽进行了一系列体外试验和药代动力学（PK）研究，以调查引入极性或带电基团时，“工程化”骨架是否能够耐受，同时保持良好的PK特征。虽然引入带电氨基酸除了保持低清除率外，还掩盖了骨架固有的PK特性，但引入极性氨基酸（即苏氨酸和吡啶基丙氨酸）导致几种环十肽表现出优异的PK特征，并且其溶解度相对于先前报道的环十肽有显著提高。
