Medicinal Chemistry Services

Case study

PRESTWICK CHEMICAL CASE STUDY

    Prestwick Chemical is a contract research organization (CRO) supporting pharmaceutical and biotechnology companies, research institutes and academic groups. We provide libraries and services for the early stage of the drug discovery process.


PRESTWICK CHEMICALmGluR4 Positive allosteric modulators

In a collaborative approach with Domain Therapeutics (Strasbourg-Illkirch, France) providing their cutting edge FRET assay technology DETECT-ALL for identifying GPCR ligands, we developed positive allosteric modulators of the metabotropic glutamate type-4 receptor (mGluR4 PAMs). Starting from one micromolar hit, within 24 months, Prestwick's medicinal chemistry team generated several families of potent and selective compounds, acting at nanomolar concentrations and presenting favorable ADME properties. One series was developed to pre-clinical candidate status, including first positive in-vivo proof of principle studies.

The collaboration involved 3 FTEs from Prestwick during 2.5 years and a patent application was filed (WO2011/051478). The program has been licensed to a major pharmaceutical company at the end to 2010 and a selected drug candidate is evaluated in phase II clinical trial in 2017.

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PRESTWICK CHEMICALAlpha-7 Nicotinic acetylcholine receptor modulators

Prestwick’s team developed for this customer the medicinal chemistry program in the hot field of Alpha-7 nAChR allosteric modulation for cognitive function recovery in neurodegenerative diseases. Two phases were successfully realized: first, the generation of innovative and potent chemical series by using pharmacophore based modeling and in silico screening; second, the multiparameter optimization of the most promising series up to the delivery of an optimized lead.
The program involved 2 FTEs on a 27 months period and led to 3 patent applications. The program has been licensed to a big pharmaceutical company in 2014 and two drug candidates coming from this work have been selected in 2017 to enter in preclinical phase.
Corresponding patents: WO 2012103583, WO 2014019023, WO 2015191799

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PRESTWICK CHEMICALC-Kit Tyrosine kinase inhibitors

    This client provided Prestwick Chemical with several families of weakly selective tyrosine-kinase inhibitors. After a short period of hit selection, we designed and synthesized selective and original c-kit tyrosine–kinase inhibitors. The newly designed compounds are active at nanomolar concentrations and present favorable ADME and toxicity profiles. Our client subsequently developed one of the compounds prepared at Prestwick, i.e. Masitinib which reached the market in 2008 in veterinary oncology. Masitinib is currently in Phase III clinical trials for the treatment of mastocytosis as a single agent, for GIST as a first-line single agent, and for pancreatic cancer in combination with another kinase inhibitor. Moreover, ten other phase III clinical trials are ongoing in oncology, inflammatory and neurodegenerative diseases.

    This collaboration involved 2 FTEs from Prestwick during 3 years.
    Corresponding patents: WO 2004014903, WO 2005073225, WO 2005040139

PRESTWICK CHEMICALOriginal anti-cancer drugs (SAPO Project)

    We started our SAR (Structure Activity Relationship) study with a micromolar active hit identified by our client. Within 12 months, we were successful in preparing a series of orally available anti-cancer drug candidates with single digit nanomolar potency. The compounds are active also against resistant carcinomas.
    Several analogs from this series have also proven active in vivo in the nanomolar range. The most advanced compound has completed Phase I and has entered Phase II clinical trial. Additional research chemistry yielded a pre-clinical backup candidate, with improved ADME-Tox and cardiovascular profiles.

    This collaboration involved 2 FTEs, then 3 FTEs from Prestwick during 5 years.
    Patents issued by this collaboration: WO2004041817, WO2005108398 and two more patents being filed.


PRESTWICK CHEMICALThe first p53/Hdm2 antagonist in clinics

    Starting from hit structures originating from our client, we have identified a series of achiral low molecular weight compounds with high solubility and a favorable pharmacokinetic profile. After a short period of affinity optimization, we focused on the optimization of ADMET profile. Our client subsequently developed one of the compounds prepared. It successfully finished Phase I.

    This collaboration involved 5 FTEs from Prestwick during 2 years.
    Corresponding patents: WO 2006032631, WO 2007107545

PRESTWICK CHEMICALNovel HIV-1 integrase inhibitors

    Starting from a validated HIV-1 integrase inhibitor with unfavorable ADMET profile and problems with its chemical stability in solution, we developed a new and original series of compounds that provided better HIV-1 integrase inhibition activity. Moreover, we optimized the ADMET profile and obtained compounds with sufficient chemical and metabolic stability. Several candidates are available for pre-clinical development. One compound has been selected for development.

    This collaboration involved 2 FTEs from Prestwick during 2 years.
    Corresponding patents: WO 2010010147, WO 2010010148, WO 2010010149


PRESTWICK CHEMICAL

Pyrrolodihydroisoquinolines as phosphodiesterase (PDE) 10 inhibitors

    Starting from a validated PDE-10 inhibitor with anti-tumor activity, we succeeded in the design and synthesis of a series of original and highly selective analogues with improved pharmacodynamic profiles. The task was accomplished in less than 2 years. Several candidates were available for pre-clinical development. Such compounds may also treat neurological disorders.

    This collaboration involved 2 FTEs from Prestwick during 20 months.
    Corresponding patents: WO2005003130, WO2005003129, WO2006075012, WO2006089815

PRESTWICK CHEMICALNovel compounds active against severe depression

    Starting from a pharmacophore-based virtual screening experiment we identified several classes of molecules that were found to re-establish a central neuronal pathway. This biochemical mechanism has been shown to be of interest for the treatment of patients with severe depression who do not respond to classical treatment.
    We selected and optimized one series of compounds and obtained molecules that were active in-vivo via oral administration.

    This collaboration involved 2 FTEs from Prestwick during 2 years.


PRESTWICK CHEMICALPotent and broad-spectrum quinolone antibiotics

    Starting from a quinolone antibiotic patented several years ago, and within a short time, we prepared several molecules satisfying the selection criteria of our client: (i) Activity on Gram+ and Gram– strains, (ii) potency higher than that of the original molecule, (iii) no interference with 5 major P450 isozymes, (iv) sufficient chemical stability and (v) reasonable water solubility.
    Two compounds have been profiled and one is in late stage animal studies for veterinary use.

    This collaboration involved 2 FTEs from Prestwick during 18 months.
    Corresponding patents: WO 2010004394, US 2010009980, EP 2145891





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