2. Academic Validation
  3. Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)

  • J Med Chem. 2018 Jun 28;61(12):5245-5256. doi: 10.1021/acs.jmedchem.8b00085.
Jon H Come 1,  Philip N Collier 1,  James A Henderson 1,  Albert C Pierce 1,  Robert J Davies 1,  Arnaud Le Tiran 1,  Hardwin O'Dowd 1,  Upul K Bandarage 1,  Jingrong Cao 1,  David Deininger 1,  Ron Grey 1,  Elaine B Krueger 1,  Derek B Lowe 1,  Jianglin Liang 1,  Yusheng Liao 1,  David Messersmith 1,  Suganthi Nanthakumar 1,  Emmanuelle Sizensky 1,  Jian Wang 1,  Jinwang Xu 1,  Elaine Y Chin 1,  Veronique Damagnez 1,  John D Doran 1,  Wojciech Dworakowski 1,  James P Griffith 1,  Marc D Jacobs 1,  Suvarna Khare-Pandit 1,  Sudipta Mahajan 1,  Cameron S Moody 1,  Alex M Aronov 1
Affiliations

Affiliation

  • 1 Vertex Pharmaceuticals Incorporated , 50 Northern Avenue , Boston , Massachusetts 02210 , United States.
PMID: 29847724 DOI: 10.1021/acs.jmedchem.8b00085
Abstract

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

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