| Literature DB >> 30044619 |
Hasane Ratni1, Martin Ebeling1, John Baird2, Stefanie Bendels1, Johan Bylund1, Karen S Chen3, Nora Denk1, Zhihua Feng4, Luke Green1, Melanie Guerard1, Philippe Jablonski1, Bjoern Jacobsen1, Omar Khwaja1, Heidemarie Kletzl1, Chien-Ping Ko4, Stefan Kustermann1, Anne Marquet1, Friedrich Metzger1, Barbara Mueller1, Nikolai A Naryshkin2, Sergey V Paushkin3, Emmanuel Pinard1, Agnès Poirier1, Michael Reutlinger1, Marla Weetall2, Andreas Zeller1, Xin Zhao2, Lutz Mueller1.
Abstract
SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.Entities:
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Year: 2018 PMID： 30044619 DOI： 10.1021/acs.jmedchem.8b00741
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446