Library of compounds labelled with radioisotope

Medicilon's pharmacokinetics department offers the clients a broad spectrum of high quality of services in the areas of in vitro ADME, in vivo pharmacokinetics and bioanalysis services, ranging from small molecules to large molecules, such as protein and antibody. The animal species involved in our services are non-human primate, canine, mice, rat, rabbit and hamster. Meanwhile, non-human primate experimental platform and isotope platform for protein/antibody are certified by the Shanghai Government. Email:marketing@medicilon.com.cn Web:www.medicilon.com

Library of compounds or their pharmaceutically acceptable salts, each compound being associated with information on its chemical identity and structure, wherein at least two of the compounds is labelled with radioisotope characterised in that the radioisotope is an AMS active radioisotope; a solid support having a compound or its pharmaceutically acceptable salt as hereindefined bound thereto, the compound being associated with information on its chemical identity and structure and comprising a radioisotope, characterised in that the radioisotope is an AMS active radioisotope as hereinbefore defined; process for the preparation of a library of compounds as claimed in any of Claims 1 to 19 comprising radioisotope labelling a plurality of compounds, each compound being associated with information on its chemical identity and structure characterised in that labelling is with an AMS active radioisotope; a kit therefor; Method for selecting one or more candidate compounds comprising screening a library of the invention comprising AMS active radioisotope labelled compounds as hereinbefore defined and obtaining a sample from the screen or submitting a compound identified for metabolic studies and obtaining a sample therefrom, and performing, AMS detection of the sample; and use of the library, a solid support comprising radioisotope labelled compound or a method as hereinbefore defined in (bio)medical, agrochemical, environmental and like screening for further study by AMS detection.

The present invention relates to a library of compounds labelled with radioisotope for detection of individual compounds, a process for the preparation thereof, a method for selecting from a library a candidate compound displaying desired characteristics and detection thereof in a simultaneous or subsequent study, and the use thereof in compound selection and detection; more particularly the invention relates to a library of compounds labelled with AMS (accelerator mass spectrometry) active radioisotope for detection of individual compounds, a process for the preparation thereof, a method for selecting from a library a candidate compound displaying desired characteristics and detection thereof by AMS; and the use thereof in compound selection, in particular in pharmaceutical drug screening, and AMS detection providing in vivo metabolism characteristics thereof.

The process of drug discovery and development for the pharmaceutical and biotechnology industries involves a host of different activities following initial selection of a number of candidate drugs, Phase 1 studies requiring scale up of drug production, preclinical toxicology, GMP manufacture, animal adsorption, diffusion, metabolism, excretion (ADME) studies etc. Before entering Phase 2 trials as many as one drug in three will have been dropped because of pharmacokinetic (PK), pharmacodynamic or toxicity issues. This process involves enormous cost which is reflected in the high costs of pharmaceuticals brought to market. Moreover the high failure rate of drug candidates further increases the cost of the successful candidates brought to market.

More recently new technologies have been adopted improving speed to market and improving initial drug candidate selection in the hope of improving the success rate during trials. For example selection of a drug may now be made from a larger number of candidates using high throughput screening of candidates in trace amounts. Moreover the candidate drugs screened may be taken from a chemical library comprising hundreds or thousands of analogue chemicals obtained from a combinatorial chemistry approach. The combinatorial chemistry approach has a further advantage in that a large number of compounds may be screened, of which the structures need not be known, the library providing structure information either in the form of a compound tag or compound number. On selection of a number of candidates from the library they are then identified and forwarded for scale up of drug production for the next stage of trials.

In addition Accelerator Mass Spectrometry (AMS) is increasingly replacing the former in vitro techniques used to indicate in vivo metabolism characteristics, giving massive improvements in accurate assessment of in vivo metabolism of compounds. This has led to the development of human microdosing (Human Phase 0) which is a revolutionary new concept which relies on the ultrasensitivity of the AMS technique.

In microdosing one or more drug candidates are taken into humans in trace doses in order to obtain early ADME and PK information. This information is then used as part of the process for selection of suitable drug candidates, to select which of the microdosed drugs has the appropriate PK parameters to take further. The low dose screening ADME studies ensure that drugs do not have to be dropped later down the development pathway because of inappropriate metabolism such as first pass, too short a half life, poor bio- availability etc. Human microdosing dramatically reduces attrition in drug candidate selection at Phase 1 trials.

Using the AMS approach it is however necessary to provide a radio labelled version of a candidate compound, after initial candidate selection by conventional means, and this requires a custom synthesis of radioiosotope labelled candidates. Although microdosing means that synthesis need be only in microdose amounts, the need for custom synthesis and scale up nevertheless provides a bottleneck in the selection method and adds greatly to costs and delays. It is therefore desirable to facilitate this stage to speed up the drug discovery process and reduce costs.

We have now surprisingly found that it is possible to provide an improved libraries comprising compounds labelled with radioisotope for use in candidate compound selection and subsequently determining the fate of the compound by detection thereof, for example detecting by its location on binding or detecting in vivo metabolism characteristics associated with individual library members. This eliminates the need for custom radioisotope labelling of selected candidate drugs at a stage in the selection procedure which effectively brings the entire selection to a halt pending the time consuming synthesis. Moreover the candidate compounds lacking the necessary metabolism characteristics may be eliminated from the drug selection at a much earlier stage dramatically reducing attrition in the selection process.

In the broadest aspect of the invention there is therefore provided a library of compounds or their pharmaceutically acceptable salts, each compound being associated with information on its chemical identity and structure, wherein at least two of the compounds is labelled with radioisotope characterised in that the radioisotope is an AMS active radioisotope.