2. Academic Validation
  3. Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1

Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1

  • Bioorg Med Chem. 2020 May 15;28(10):115481. doi: 10.1016/j.bmc.2020.115481.
Andrew Fensome 1,  Catherine M Ambler 2,  Eric Arnold 2,  Mary Ellen Banker 2,  James D Clark 3,  Martin E Dowty 4,  Ivan V Efremov 4,  Andrew Flick 2,  Brian S Gerstenberger 4,  Roger S Gifford 3,  Ariamala Gopalsamy 4,  Martin Hegen 3,  Jason Jussif 3,  David C Limburg 2,  Tsung H Lin 3,  Betsy S Pierce 2,  Raman Sharma 2,  John I Trujillo 2,  Felix F Vajdos 2,  Fabien Vincent 2,  Zhao-Kui Wan 4,  Li Xing 4,  Xiaojing Yang 4,  Xin Yang 2
Affiliations

Affiliations

  • 1 Medicine Design, Pfizer Inc, 1 Portland Street, Cambridge, MA 02139, United States. Electronic address: Andrew.Fensome@Pfizer.Com.
  • 2 Medicine Design, Pfizer Inc, Eastern Point Road, Groton, CT 06340, United States.
  • 3 Inflammation and Immunology, Pfizer Inc, 1 Portland Street, Cambridge, MA 02139, United States.
  • 4 Medicine Design, Pfizer Inc, 1 Portland Street, Cambridge, MA 02139, United States.
PMID: 32253095 DOI: 10.1016/j.bmc.2020.115481
Abstract

Herein, we disclose a new series of Tyk2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.

Keywords

Arthritis; Autoimmune; Inflammation; JAK1; Kinase; Psoriasis; TYK2.

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