Peptidic Drugs

Written by Dr. Martin Flegel

Since the early 1950s, the research of peptides at the Institute of Organic Chemistry and Biochemistry (IOCB) of the Czechoslovak Academy of Sciences has focused on the Neurohypofyseal hormones – their synthesis and biological effects. When Vincent du Vigneaud received his Nobel Prize in 1955 for his pioneering synthesis of Oxytocin and Vasopressin, the research in this field at the IOCB considerably progressed and almost reached the goal of being the first in the industrially applicable synthesis of Oxytocin.

In 1958, the industrial production of synthetic Oxytocin started at the Leciva-Pharmaceuticals company.

Peptidic drugs formula 1

In about two years, Lysin-vasopressin (LVP) was put into production at the same pharmaceutical company.

Peptidic drugs formula 2

Oxytocin was and still is used as the basic drug in gynecology during childbirth; Lysin-vasopressin was originally used in the treatment of diabetes insipidus, but its side effects (pressoric activity and myocardial toxicity) have prevented its broad utilization in this treatment. Nowadays, it is still used at low concentrations in dentistry (as an additive to local anesthesia).

The research which has continued at the IOCB’s peptide department and structure-activity studies have enabled the rational replacement of amino-acid residues in various positions of above-mentioned hormone structures and the preparation of new analogues of hormones without the undesirable effects.

Oxytocin could be replaced in obstetrics-gynecology applications by Metyloxytocin

which was safer in the cases when protracted delivery took place; unfortunately, due to marketing problems, the production of this drug was rather low and stopped.

Another excellent OT analogue, Carbetocin, was synthesized later. Despite its very promising biological activity profile and at the same time enhanced stability, this peptide was used for many years as a veterinary drug only. In the last ten years have been exploited its very suitable and useful properties in human medicine.

Carbetocin have been registered by Ferring for human use as Duratocin in Canada during 1996-7. Later on registration has been reached in EU as well, for the treatment and facilitation of protracted delivery labours.

Peptidic drugs formula 4

Deamino-carba1-2-O-metyltyrosine-Oxytocin (Carbetocin)

In the group of “vasopressin-like” peptides, the research has focused on the both anti-diuretic and pressoric activities and their selectivity. The extension of the peptide sequence of LVP at the N-terminal part resulted in a compound named Glypressin or Terlipressin.

Peptidic drugs formula 5

The very protracted and low pressoric activity of this analogue is currently being used for the treatment of bleeding from gastric and duodenal ulcers and also for the treatment of esophageal varices.

The most successful analogue of Arginin-vasopressin has been prepared by substitutions of L-Arg in position 8 by D-Arginin and at the same time in position 1, where Cysteine was substituted by 3-mercaptopropionic acid (Mpa). In this way, a compound having very high specific antidiuretic and very negligible pressoric activity was obtained:

Peptidic drugs formula 6

1-deamino-8-D-arginin-vasopressin (DDAVP) Desmopressin

DDAVP is nowadays broadly used drug for the treatment of diabetes insipidus, enuresis nocturna, Hellebrand disease and other bleeding hemophilic-like disorders. No doubt Desmopressin can be considered as the highlight and blockbuster of the IOCB and in many aspects (including economical) the most successful story of peptide research at the IOCB.

All of the above-mentioned peptide drugs were produced in Czechoslovakia at the Leciva SPOFA pharmaceutical company and after 1989 at Czech subsidiaries of Ferring and Polypeptide Laboratories companies.

It is necessary to note that Desmopressin, Terlipressin and Carbetocin were licensed by the Czechoslovak Academy of Sciences to the Swedish firm Ferring AB in the late sixties. All three compounds are nowadays produced as bulk pharmaceutical chemicals at the Polypeptide Laboratories group mainly in Scandinavia and India in very large several ten-kilo quantities, and Desmopressin is the diamond and flagship among the peptide drugs produced worldwide at present.

Behind the peptide research at the IOCB, there were mainly three excellent peptide chemists, who were carrying out the scientific research and development of the above mentioned peptide drugs and whose names should be mentioned here:

Prof. Josef Rudinger and Dr. Milan Zaoral and Dr. Karel Jost.

All three men were excellent peptide and organic chemists, and for this reason peptide chemistry in our country reached the highest and internationally recognized level during their life and later. Needless to mention, there were many others peptide organic chemists and biochemists at IOCB involved in this interesting and fruitful peptide field. Some of them cooperated strongly to industrial research, which made possible later on the full development of interesting peptide molecules in to the patented active pharmaceutical ingredients.

Most of peptide chemists are also members of the European Peptide Society (EPS). This society organizes European peptide symposium, which is held every two years in a nominated European country. The very first EPS was organized by Prof. Josef Rudinger in Prague in 1958 and tradition of these large meetings is maintained till the present days. European Peptide Society is awarding excellent peptide chemists with the “Rudinger Award “ for lifelong work in the peptide field. Other highly recognized awards given by EPS are “Leonidas Zervas” and “Miclós Bodanszky” awards for the nominated excellent peptide scientists. These chosen scientists then have the privilege to give a very honoured lecture during the EPS symposia.