Lead optimization services
The WIL Research Company (WRC) has extensive experience in fast track tailor-made screening strategies to help you with the challenging task of selecting your best candidate drug. By combining excellent project communication and support from our cooperating team of experts with rapid turnaround times, we are able to shorten time to market for your next lead compounds. Lead optimization strategy From early phase chemistry, through in vitro toxicity screening and metabolism profiling, to establishing in vivo bioavailabi lity; we put facilities and expertise, state-of-the-art equipment and high quality accommodations at your disposal. No standard strategy exists that is suitable for the lead optimization of developmental drugs. Therefore, our first focus in assisting you with lead optimization is not to screen a high number of compounds with as many screening studies as possible, but to start designing your most efficient and effective drug screening strategy that addresses major aspects of ADMET. Discovery is more than a chance event, it is a planned effort After determining the lead optimization screening strategy that fits best with your compound portfolio, the details of the different study protocols are discussed in close collabo ration. The only thing you need to worry about is getting the compounds delivered to WRC. You receive the results within the agreed timelines and will be able to select or flag compounds in very short turnaround times.
1. Physical chemistry assessment - solubility - stability - selection of salt forms - chemical/physical characterization 2. ADME screening (in vitro / in vivo) - CYP inhibition - CYP induction - Metabolism - Drug drug interactions - Plasma protein binding - Permeability (PAMPA, Caco-2) - Metabolic stability - Metabolite profiling and identification - Rapid PK / PD screening (in vivo) 3. Toxicology profiling (in vitro) - Genotoxicity screening (AMES II, microames, Greenscreen, clastogeni city in human cells) - Comet assay - 3T3-NRU-phototoxicity - Cytotoxicity endpoints in human cell lines or hepatocytes - HET-CAM - BCOP - herg screening - Skin irritation assay - Skin corrosion - Skin absorption 4. Candidate selection (in vivo) - Pharmacological screening e.g. Irwin observational assessment, drug abuse liability, endocrine function - Pharmacokinetics (rodents, dogs, monkeys) with fast turnaround - Toxicology screening with expedited histopathology - Cardiovascular screening (telemetry) - Safety biomarkers - Early immunogenicity assessment for protein candidates - Fast and efficient development of bioanalysis methods Menu selection of some available screening assays The screening assays described above will help you ensure that your selected compound will be a successful drug. The exact strategy of screening is determined in close collaboration and will be dependent on your drug portfolio. Q: We have a portfolio of approximately 50 compounds. How to downsize this portfolio to three compounds? A: Example of in vitro screening assays CYP inhibition screening Objective IC 50 determination in a high throughput screening environment using pooled human liver microsomes, probe substrates and reference inhibitors for CYP1A2, 2C8, 2C9, 2C19, 2D6, 3A4 (testosterone) and 3A4 (midazolam). Reversible and time-dependent inhibition is investigated. Deliverables Sponsor: send selected number of compounds per week including information on molecular weight. WRC: Performs IC 50 experiments (reversible and time-dependent) for all CYP isoforms. LC-MS analysis of incubated samples (validated assays for probe substrates and metabolites) Determine fold-shift in IC 50 (reversible) and IC 50 (time dependent) to determine possible time dependent inhibitor(s). Report results of all compounds per batch in one spreadsheet (graphic presentation, IC 50 values, fold shift values and red / yellow / green flag).
Project workflow CYP inhibition screening (reversible and time-dependent inhibition) Week 0: Phone call detailing number of compounds Week 1: - Compound delivery - CYP inhibition experiments Week 2: - Experiments continued REPORT Turnaround time: 2 weeks Example of graphic presentation of results (in spreadsheet format) % of control activity % of control activity 70.0 60.0 50.0 40.0 30.0 20.0 10.0 120.0 100.0 80.0 60.0 40.0 20.0 Test compound X, CYP3A4 (midazolam) DI serie 1 DI serie 2 TDI serie 1 TDI serie 2 0.0 1.E-08 1.E-07 1.E-06 1.E-05 1.E-04 Concentration (M) Test compound Y, CYP1A2 0.0 1.E-08 1.E-07 1.E-06 1.E-05 1.E-04 Concentration (M) DI serie 1 DI serie 2 TDI serie 1 TDI serie 2 Example of in vivo screening assays - oral rat screening Objective T max, C max and AUC determination for a selected number of compounds per batch using 2 rats (various strains) per compound with a minimum of interaction / reporting / administration process via standardized protocol. Deliverables Sponsor: send selected number of compounds per week including molecular weight/conformation. WRC: Pretest analytical method for each individual compound Dosing (oral, 2 rats per compound) Analyze up to 6 PK samples using a generic LC-MS/MS method Report results with simple spreadsheet
Project workflow oral PK screening Week 0: Phone call detailing number of compounds Week 1: - Compound delivery - Preparation of formulation - LC-MS feasibility check Week 2: - Dosing REPORT Turnaround time: 2 weeks Overview on number of compounds screened in oral PK screen (2009) Oral rat PK screen (220 compounds/9 months) 80 250 # compounds 60 40 20 200 150 100 50 cumulative # compounds 0 mar apr may jun jul aug sep oct nov aug month 0