Inventiva’s paper on the discovery and synthesis of its panPPAR agonist lanifibranor accepted and published in the Journal of Medicinal Chemistry of the American Chemical Society
March 13, 2018
Lanifibranor is in Phase IIb development for non-alcoholic steatohepatitis (NASH) and systemic sclerosis (SSc)
Daix (France) March 13, 2018 – Inventiva, a biopharmaceutical company developing innovative therapies in nonalcoholic steatohepatitis (NASH), systemic sclerosis (SSc) and mucopolysaccharidosis (MPS), today announced the publication of an article online, ahead of print, describing the discovery of its promising panPPAR agonist, lanifibranor, in the Journal of Medicinal Chemistry of the American Chemical Society. The Journal of Medicinal Chemistry is one of the most important journals in medicinal chemistry.
Pierre Broqua, Chief Scientific Officer and Inventiva’s co-founder, said: “We’re delighted to have our paper published by the prestigious Journal of Medicinal Chemistry. Of particular interest is the data showing how lanifibranor has a specific binding into the PPAR pocket, a further explanation to the excellent safety profile demonstrated so far by lanifibranor, our lead clinical candidate currently in Phase IIb trials in NASH and SSc.”
Peroxisome proliferator-activated receptors (PPARs) play a key role in controlling the fibrotic process. Inventiva’s lead program lanifibranor is an anti-fibrotic treatment with a powerful mechanism of action that activates all three alpha, gamma and delta PPARs. Currently two lanifibranor Phase IIb trials are ongoing in NASH and SSc. Inventiva has been granted orphan drug designation for lanifibranor in the treatment of SSc by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
Journal of Medicinal Chemistry publication
The study now published in the Journal of Medicinal Chemistry sets out in detail how Inventiva’s research team discovered lanifibranor, and what they believe are the benefits of this novel compound.
Starting from a high-throughput screening hit, an extensive medicinal chemistry optimization campaign led to the discovery of lanifibranor. Xray co-crystal structure of lanifibranor bound to PPARdisplayed a new atypical binding mode in comparison to rosiglitazone. The compound’s head to tail positioning stabilizes a conformationally active form of PPARwithout interacting directly with Helix H12. The authors believe that lanifibranor’s non-classical binding mode, its different coregulator recruitment profile and its balanced activity for the three PPAR isoforms may well explain its good safety profile relative to other PPAR agonists.
Furthermore, lanifibranor demonstrated excellent anti-hyperglycemic and hypolipidemic efficacy in a relevant mouse model, and a significant anti-fibrotic activity in a mouse model for liver fibrosis. Compared to other PPAR agonists, lanifibranor had no effect on hematocrit, plasma volume or heart weight in rats. These encouraging results provide ample rationale for the further development of lanifibranor in NASH.
Link to publication & reference:
Design, synthesis and evaluation of a novel series of indole sulfonamide Peroxisome Proliferator Activated Receptors (PPAR)α/δ/γ triple activators: discovery of lanifibranor a new anti-fibrotic clinical candidate https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01285
J. Med. Chem., DOI: 10.1021/acs.jmedchem.7b01285
Lanifibranor, its lead product, is an anti-fibrotic treatment acting on the three alpha, gamma and delta PPARs (peroxisome proliferator-activated receptors), which play key roles in controlling the fibrotic process. Its anti-fibrotic action targets two initial indications with substantial unmet medical need: NASH, a severe and increasingly prevalent liver disease already affecting over 30 million people in the United States, and systemic sclerosis, a disease with a very high mortality rate and for which there is no approved treatment to date.
Inventiva is also developing a second clinical program with odiparcil (IVA 336) for the treatment of patients with mucopolysaccaridosis type VI (or Maroteaux-Lamy syndrome), a rare and severe gene disease affecting children. Odiparcil has also the potential to address other MPS types, characterized by the accumulation of chondroitin or dermatan sulfate (MPS I or Hurler/Sheie syndrome, MPS II or Hunter syndrome, MPS IVa or Morquio syndrome and MPS VII or Sly syndrome). Inventiva is also developing a portfolio of early research projects in the field of oncology.
Inventiva benefits from partnerships with world-leading research entities such as the Institut Curie in the field of oncology. Two strategic partnerships have also been established with world-class major pharmaceutical companies AbbVie and Boehringer Ingelheim in the fields of autoimmune diseases (specifically in psoriasis) and fibrosis respectively. These partnerships provide milestone payments to Inventiva upon the achievement of pre-clinical, clinical, regulatory and commercial milestones, in addition to royalties on the products resulting from the partnerships.
Inventiva employs over 100 employees and owns R&D facilities near Dijon, acquired from the international pharmaceutical group Abbott. The Company owns, a proprietary chemical library of over 240,000 molecules as well as integrated biology, chemistry, ADME and pharmacology platforms.
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