Pharmacokinetic Studies around the Mono‐ and Difunctionalization of a Bioavailable Cyclic Decapeptide Scaffold

Abstract

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.

Drug‐Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side‐Chain Lipophilicity

“…We designed two cyclic peptomer scaffolds based on aseries of highly cell permeable and orally bioavailable cyclic decapeptides. [10] Va riants of this scaffold such as 1 (Figure 1a) are similar to the natural product gramicidin Si nw hich solvent-exposed amides are capped with N-methyl groups.Nmethylation eliminates the desolvation penalty associated with exposed backbone amides while preserving the intramolecular hydrogen bonding network of the natural product. TheF ouchØ peptide also shares the same pattern of stereocenters and overall architecture as the previously described cyclic hexapeptide 1NMe3.…”

“…[15] LPE, defined specifically by the equation LPE = logD(dd/ w)À1.06AlogP + 5.47, represents as caffoldsi ntrinsic membrane permeability by normalizing its membrane partitioning against its bulk lipophilicity. [10] Compound 1 is aside-chain variant with exceptional oral bioavailability (> 100 %). b) Peptoid (X 1 and X 2 )a nd peptide (X 3 ) building blocks used in the synthesis of Libraries Aand B. c, d) Designs for cyclic peptomer Libraries A( c) and…”

“…FouchØ,e tal.,r ecently reported ah ighly membrane permeable cyclic decapeptide which showed that favorable ADME and PK properties can be achieved in synthetic cyclic peptides with molecular weights above 1000 Da (Figure 1a). [10] Since peptoids are derived from primary amines and can therefore extend the range of chemical functionality that can be incorporated into ac yclic peptide, [11] we initially set out to determine whether permeability could be maintained in this system upon substitution with peptoid residues. Serendipitously,w ef ound that peptoid substitutions in these macrocycles had as pecific effect on conformational flexibility,s uch that solvent-dependent chameleonicity could be tuned depending on the location of the peptoid substitutions within the scaffold.…”

Modulation of Oral Bioavailability and Metabolism for Closely Related Cyclic Hexapeptides

“…Previous reports demonstrated how multiple N -methylation and matched hydrogen bond pairs across the macrocycle (White et al 2011 ; Nielsen et al 2014 ; Fouche et al 2016a , b ) could improve oral bioavailability. In this study, we have shown how hydrophobic shielding can contribute to masking polarity, and thereby enhancing permeability, while simultaneously providing excellent solubility.…”

Pyridyl-Ala Modified Cyclic Hexapeptides: In-Vitro and In-Vivo Profiling for Oral Bioavailability

“…On the other hand, a publication appeared, which according to cellular tests did not support the 2-Pal residue as a suitable modification, but in this case no in vivo studies were performed (Thansandote et al 2015). While this more systematic work was in progress, our colleagues published on positive effects of 2-Pal modified cyclic decamers with respects to oral uptake (Fouche et al 2016). Since fine-tuning of properties is of particular importance for macromolecules designed for oral bioavailability, we decided to study various Pal residues incorporated in the same cyclic hexapeptide scaffold in more detail.…”