Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules
| Autor: | Philip L. Smith, A. Nichols, Thomas W. Ku, William E. Bondinell, Glynn Wilson, J. Samanen, Chao-Pin Lee, Gerald R. Rhodes |
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| Rok vydání: | 1996 |
| Předmět: |
Pharmacology
chemistry.chemical_classification Oligopeptide Ussing chamber Myocardial Infarction Administration Oral Biological Availability Pharmaceutical Science Transporter Peptide Intestinal absorption Absorption Cerebrovascular Disorders Intestinal Absorption Biochemistry chemistry Oral administration Drug Design Paracellular transport Pharmacophore Peptides Platelet Aggregation Inhibitors |
| Zdroj: | Journal of Pharmacy and Pharmacology. 48:119-135 |
| ISSN: | 2042-7158 0022-3573 |
| DOI: | 10.1111/j.2042-7158.1996.tb07111.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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