Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

Abstract

This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in-vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone-releasing peptide SK&F 110679 and two GPIIb/IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure-transport studies are reviewed for this transporter. The tools for studying oral drug absorption in-vivo involve animals bearing in-dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided. The review concludes with two chemical strategies that may be taken towards the enhancement of oral bioavailability of peptidergic molecules. The first strategy involves the chemical modification of peptides which enhance intestinal permeability, specifically the modification of amide bonds. The second strategy involves the design of compounds bearing nonpeptide templates, which are more amenable to the discovery of compounds with oral activity, from peptide pharmacophore models. An example is given regarding the discovery of SB 208651, a potent orally active GPIIb/IIIa antagonist, designed from the peptides SK&F 106760 and SK&F 107260.

Past, Present, and Future Technologies for Oral Delivery of Therapeutic Proteins

“…102,108,109 Changes can be made in lipophilicity, charge, molecular size, solubility, configuration, isoelectric point, chemical stability and affinity to carriers to enhance absorption and systemic circulation. Two specific approaches were made for oral peptide delivery using chemical modification of peptide amide bond to enhance intestinal permeability and the design of compounds bearing nonpeptide templates.…”

Human Jejunal Effective Permeability and Its Correlation with Preclinical Drug Absorption Models

“…Furthermore, it has been reported by Chikhale et a1 (1994) that the hydrogen bonding capacity of small peptides is one of the major factors determining the permeability across the Caco-2 monolayer and the blood-brain barrier in-vitro and insitu, in rats (Conradi et a1 1992;Chikhale et al 1994;Burton et a1 1996;Samanen et al 1996). Consequently, there is a need for studies of the relationship between measured physicochemical properties for compounds with a wide range of chemical structures and in-vivo permeability across biological membranes.…”

Spirobicyclic diamines. Part 3: Synthesis and metal complexation of proline-derived [4.4]-spirodiamines

“…In some cases this has been used in biologically active molecules to either increase the affinity of the molecule for its target (cyclic versus acyclic peptides), 3 or to make the molecules more metabolically stable, which can lead to improved bioavailability. 4 The naturally occurring polycyclic diamine (-)-sparteine (3) has found use as a chiral ligand in a number of applications in asymmetric synthesis.…”

“…4 The naturally occurring polycyclic diamine (-)-sparteine (3) has found use as a chiral ligand in a number of applications in asymmetric synthesis. 5 Another method of constraint which has been used is to introduce a spiro fusion of two rings which forces the nitrogen atoms into a mutually orthogonal relationship (4, Figure 1).…”