Method for screening and producing compound libraries

• US 6,996,473 B2
• Filed: 11/21/2001
• Issued: 02/07/2006
• Est. Priority Date: 09/14/1998
• Status: Expired due to Fees

• Current Assignee: Lion Bioscience AG (2invest AG)
• Original Assignee: Lion Bioscience AG (2invest AG)
• Inventors: Sinko, Patrick J., Norris, Daniel A., Grass, George M., Wehrli, John E., Leesman, Glen D.
• Primary Examiner(s): Moran, Marjorie A.
• Application Number:
  US09/989,533
• Publication Number:
  US 20020061540A1
• Time in Patent Office: 1,539 Days
• Field of Search: 702/19, 702/30, 703/2, 703/11, 703/3
• US Class Current: 702/19
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: G16B 35/00 ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides
• CPC Class Codes: G16C 20/60 In silico combinatorial chemistry
• CPC Class Codes: G16C 20/62 Design of libraries
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

A secondary compound library produced by a method of screening a compound library or portion thereof by absorption is provided. The method includes a step (i) that screens a primary compound library or portion thereof having a plurality of test samples containing isolated compounds or isolated mixtures of compounds per test sample by generating an in vivo absorption profile for each of the test samples from initial dose data and from in vitro bioavailability data comprising permeability and solubility data for each of the test samples, wherein the absorption profile includes at least one of rate of absorption, extent of absorption, and concentration of a test sample. Step (ii) produces a secondary compound library that includes at least one compound from the primary compound library having a desired absorption profile.

Claims

1. A method of screening a compound library or portion thereof by absorption, the method comprising:

providing a computer-implemented pharmacokinetic tool comprising an input/output system and a physiological model of a mammalian system of interest;

the model comprises a selected adjustment parameter and the selected adjustment parameter comprises a value obtained by;

(i) assigning an initial value to the selected adjustment parameter;

(ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;

(iii) comparing the output data with second data for the plurality of compounds;

(iv) selecting a new value for the selected adjustment parameter such that deviation of the comparison in step (iii) is reduced; and

(v) replacing the value of the selected adjustment parameter in the model with the new value selected in step (iv);

providing in vitro permeability and solubility data for a plurality of test samples from the compound library or portion thereof to the computer-implemented pharmacokinetic tool;

providing initial dose data to the computer-implemented pharmacokinetic tool;

generating a predicted in viva absorption profile for each of the plurality of test samples with the computer-implemented pharmacokinetic tool; and

based on the generated absorption profiles, producing a secondary compound library comprising compounds having a desired absorption profile, whereby the compound library or portion thereof is screened by absorption.

2. The method of claim 1, wherein said physiological model is a mathematical model of said mammalian system comprising as operably linked components:

equations for calculating solubility and absorption of a test sample for one or more physiological segments of the mammal system of interest; and

initial parameter values for the equations corresponding to physiological parameters and one or more selectively optimized adjustment parameters for one or more physiological segments of said mammal system of interest.

3. The method of claim 1, wherein said permeability data is derived from a cell-based assay.

4. The method of claim 3, wherein said solubility and said dissolution rate data is derived from a chemical-based assay.

5. The method of claim 1, wherein said mammalian system of interest is selected from the group consisting of the gastrointestinal tract, the eye, the nose, the lung, the skin, and the brain.

6. The method of claim 1, wherein said compound library is selected from the group consisting of a natural library, a synthetic library, and a combinatorial library.

7. The method of claim 1, wherein said physiological model is for a mammalian system selected from the group consisting of gastrointestinal tract, eye, nose, lung, skin, and blood brain barrier.

8. The method of claim 1, which further comprises:

generating one or more predicted in vivo pharmacokinetic properties in addition to the absorption profile for the plurality of test samples;

selecting compounds by one or more of said properties; and

producing one or more compound libraries characterized by absorption, and one or more of said properties.

9. The method of claim 8, wherein said one or more properties in addition to absorption is selected from the group consisting of metabolism, toxicity and activity.