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Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

Perry MWD, Björhall K, Bold P, Brűlls M, Börjesson U, Carlsson J, Chang HA, Chen Y, Eriksson A, Fihn BM, Fransson R, Fredlund L, Ge H, Huang H, Karabelas K, Lamm Bergström E, Lever S, Lindmark H, Mogemark M, Nikitidis A, Palmgren AP, Pemberton N, Petersen J, Rodrigo Blomqvist M, Smith RW, Thomas MJ, Ullah V, Tyrchan C, Wennberg T, Westin Eriksson A, Yang W, Zhao S, Öster L
J Med Chem 64 8053-8075 (2021)
Related entries: 7oi4, 7oij, 7ois

Cited: 7 times
EuropePMC logo PMID: 34080862

Abstract

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

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Reviews citing this publication (3)

  1. PI3K inhibitors are finally coming of age. Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. Nat Rev Drug Discov 20 741-769 (2021)
  2. The role of PI3Kγ in the immune system: new insights and translational implications. Lanahan SM, Wymann MP, Lucas CL. Nat Rev Immunol 22 687-700 (2022)
  3. Pd-Catalyzed Cross-Couplings: On the Importance of the Catalyst Quantity Descriptors, mol % and ppm. Horbaczewskyj CS, Fairlamb IJS. Org Process Res Dev 26 2240-2269 (2022)

Articles citing this publication (3)

  1. Design, Synthesis, and Development of pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part I-Indole Derivatives. Stypik M, Zagozda M, Michałek S, Dymek B, Zdżalik-Bielecka D, Dziachan M, Orłowska N, Gunerka P, Turowski P, Hucz-Kalitowska J, Stańczak A, Stańczak P, Mulewski K, Smuga D, Stefaniak F, Gurba-Bryśkiewicz L, Leniak A, Ochal Z, Mach M, Dzwonek K, Lamparska-Przybysz M, Dubiel K, Wieczorek M. Pharmaceuticals (Basel) 15 949 (2022)
  2. Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model. Zhang X, Dai Q, Shan J, Zhang S, Zhang B, Liu S, Zhang Y, Wang Y, Li X, Jin X, Liang D, Ding J, Wang Y, Wen Y. Exp Ther Med 25 225 (2023)
  3. Medicinal Polypharmacology in the Clinic - Translating the Polypharmacolome into Therapeutic Benefit. Rafehi M, Möller M, Ismail Al-Khalil W, Stefan SM. Pharm Res 41 411-417 (2024)


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