In vivo Lead Generation

We aid your search for new chemical matter for challenging targets. This endeavour will be achieved with insight from our rich life science database and extensive in-house expertise, together with our Digital Life Science team. Our long translational experience spans from target to clinical molecules.

best-in-class life science chemistry capabilities

Efficient design and synthesis of high-quality test compounds and chemical probes.

Close interaction with lead discovery in screening hit-list evaluation and long-standing expertise in the Hit-2-Lead process (hit selection, assessment and modification).

Rapid development of different cluster into viable lead structures to fit your lead structure profile.

Strong drug-hunting attitude within the Lead-2-Candidate process, short cycle-times in multi-dimensional lead optimization programs.

optimisation of molecular properties is a team effort

Close collaboration with computational compound design, therapeutic research functions (in vitro-, ex-vivo, in vivo studies for your target/ indication of interest) and preclinical compound profiling (DMPK property optimization) to identify a preclinical candidate according to an agreed target product profile.

Application of state-of-the-art methodologies (photochemistry, electrochemistry, final stage diversification) to quickly synthesize the target compounds of interest.

First-rate expertise in new modalities (e.g. PROTACs, ADCs) and modalities beyond small molecules (e.g. peptides).

In our Separation Technology Labs (STL) we can perform fast automated as well as customized purification of drug candidates and intermediates, using a variety of different methodologies such as SFC or MS-guided automated preparative HPLC.

Separation of stereoisomers on analytical or preparative scale can also be provided.

We offer the whole range of efficient and flexible small sample single applications and/or batch-wise purifications of test compounds and intermediates.

Employing Nature’s toolbox for production of proteins and plasmids as well as for chemical biotransformations on a preparative scale.

Protein and plasmid production capabilities (1-100 L steel fermenters, shaking incubators, Wave-bioreactors for insect cell cultivation) to support your lead discovery activities.

Unique and broad collection of wild-type fungi & bacteria strains (2000), E. coli or S. pombe strain expressed hCYPs (500) as well as CYP102A1 (BM3) mutants (300) especially for redox biotransformations and metabolite synthesis.

We screen in 24 and 96 deep well plates and can produce metabolites of candidates and intermediates (milligram- to gram scale)

Our comprehensive collection of Streptomyces bacteria allows for the biocatalytic synthesis of glucuronides of clinical candidates.

NUVISAN owns a broad and unique collection of over 2000 fungi & bacteria strains, close to 400  E. coli or S. pombe strains expressing hCYPs as well as over 350 CYP102A1 (BM3) mutants especially used for oxidative drug metabolite synthesis. In addition, our comprehensive collection of Streptomyces bacteria allow us to biocatalyticly synthetize glucuronides.

As a first step we commonly offer a Metabolite Screening with 4 top panels in 24 and 96 deep well plates for identification of metabolite producing strains. Optionally, we can expand for a screening of chemical oxidation and glucuronidation methods and a wider range of our inhouse-strain collection.
As a second step we can proceed with a Microbial Metabolite Processing including scale-up to a 10 L fermenter, work-up, purification and structure elucidation. Optionally, we offer metabolite synthesis by chemical oxidation or glucuronidation or de novo synthesis.
As a third step Microbial Metabolite Scale-up can be conducted in up to 100 L fermenters to produce drug metabolites on milligram- to gram scale.

Optionally, NUVISAN provide Metabolite identification and structure elucidation by LC-HRMS in various biological matrices as well as confirmation of identity of synthesized metabolites with desired drug metabolites from in vitro or in vivo samples.

The characterization of ADME properties of SMOL molecules is an essential process to identify suitable lead structures for non-clinical in vivo studies and to achieve the best possible starting point for the lead optimization process. Our in vitro compound profiling services include standardized assays or custom designed assays for metabolic stability (liver microsomes and hepatocytes), permeability and transporters, plasma protein binding, blood-plasma ratio, reversible CYP inhibition in major isoforms, irreversible inhibition in CYP3A4, CYP induction (HepaRG cells), phenotyping of drug metabolizing enzymes (CYPs, UGTs and non-CYPs), metabolite identification and structure elucidation (e.g. from hepatocytes, microsomes).

We perform high quality Pharmacokinetic (PK) studies in mice and rats with micro-sampling from jugular-vein cannulated animals to complete PK profiles per animal. Depending on your compound profile and needs, our capabilities offer various study designs. Available administration routes are intravenous (bolus and infusion) and oral (intragastral). Dosing of molecules may be in cassette (up to 3 molecules in 1 study) or as mono compound dosing. Tailor-made mechanistic studies for specific ADME questions can be provided: tissue distribution studies (cold compound) including excreta from the same animal, bile duct-cannulated rats, compound administration via portal vein infusion. Relative bioavailability (formulation research). Automated blood sampling is also possible for specific questions. State-of-the-art animal welfare standards.

In addition to the cannulated rodents, NUVISAN can offer similar studies in non-cannulated rodents. Moreover, NUVISAN can help your development programs with discovery and development pharmacokinetic studies in dog and minipig.  

Our bioanalytical services at NUVISAN Berlin comprise fast turnaround non-GLP LC-MS/MS analysis for small molecules in various biological matrices, which can be part of a complete in vivo PK or safety study package, or also after delivery of samples by the customer. Manual and semi-automated sample preparation of plasma and tissues are used together with our modern UPLC-MS/MS equipment for highly sensitive and selective quantitation of drug, known metabolites and biomarkers. Regulated bioanalysis (GLP and GcLP) services can also be provided by our sites in Neu-Ulm and Sophia Antipolis.

In addition, our platform offers high resolution MS (HRMS) capabilities for the identification and structural elucidation of metabolites. Depending on your needs we perform quick metabolic hot spot analysis for structure optimization, in depth metabolite identification and profiling from in vitro and in vivo, evaluation of biotransformation pathways in various species and tissue fractions as well as assessment of reactive metabolites. NUVISAN also offers metabolite investigation in samples from first in human studies (FIM) and in samples originating from radiolabelled in vitro and in vivo studies studies.

 

The genotoxic potential of a compound can be evaluated in bacteria as well as in mammalian cells. DNA crosslinks, oxidative DNA damages or point mutations are identified with the help of the bacterial reverse mutation test (Ames Test).  The test is either conducted in a plate format, which allows for the determination of cytotoxicity or in a high-throughput screening manner in a 384-well format using pipetting robots. In order to determine the clastogenic and aneugenic potential of a compound the flow cytometry based micronucleus test is conducted.  V79 cells are exposed to the test compound and modern flow cytometers and automated sample handling systems ensure utmost precision in micronuclei detection. An exogenous metabolic activation is employed for both test systems to exclude the possibility that a metabolic activation of the substance produces genotoxic intermediates.

NUVISAN can offer a wide repertoire of different in vitro as well as in vivo models supporting the biological understanding of your research programs and to unravel molecular drivers of efficacy. We establish and implement novel mechanistic cellular assays to support and enable lead optimization screening. Early insights into the Mode of Action of the drug candidates help to de-risk projects by ensuring on-target drug activity. We identify target engagement / pharmacodynamic biomarkers based on in-depth studies of the target biology using literature searches as well as bioinformatic analyses.

Demonstrating on-target activity of the candidate in pharmacologically relevant in vivo models is a key step during in vivo Lead Generation.
These studies provide further confidence into the Mode of Action and support pharmacokinetic optimization efforts of the candidate.

Demonstrating efficacy of the candidate in pharmacologically relevant in vivo models is an additional key step during in vivo Lead Generation. These studies provide further confidence into the Mode of Action and support pharmacokinetic optimization efforts of the candidate.