2. Academic Validation
  3. Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist

Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist

  • J Med Chem. 2018 Dec 13;61(23):10415-10439. doi: 10.1021/acs.jmedchem.8b00392.
Mark E Schnute,  Mattias Wennerstål 1,  Jennifer Alley,  Martin Bengtsson 1,  James R Blinn,  Charles W Bolten,  Timothy Braden,  Tomas Bonn 1,  Bo Carlsson 1,  Nicole Caspers 2,  Ming Chen 2,  Chulho Choi 2,  Leon P Collis,  Kimberly Crouse,  Mathias Färnegårdh 1,  Kimberly F Fennell 2,  Susan Fish,  Andrew C Flick 2,  Annika Goos-Nilsson 1,  Hjalmar Gullberg 1,  Peter K Harris,  Steven E Heasley 2,  Martin Hegen,  Alexander E Hromockyj,  Xiao Hu,  Bolette Husman 1,  Tomasz Janosik 1,  Peter Jones,  Neelu Kaila,  Elisabet Kallin 1,  Björn Kauppi 1,  James R Kiefer,  John Knafels 2,  Konrad Koehler 1,  Lars Kruger 1,  Ravi G Kurumbail 2,  Robert E Kyne Jr 2,  Wei Li,  Joakim Löfstedt 1,  Scott A Long,  Carol A Menard 2,  Scot Mente,  Dean Messing,  Marvin J Meyers,  Lee Napierata,  Daniel Nöteberg 1,  Philippe Nuhant 2,  Matthew J Pelc,  Michael J Prinsen,  Patrik Rhönnstad 1,  Eva Backström-Rydin 1,  Johnny Sandberg 1,  Maria Sandström 1,  Falgun Shah,  Maria Sjöberg 1,  Aron Sundell 1,  Alexandria P Taylor 2,  Atli Thorarensen,  John I Trujillo 2,  John D Trzupek,  Ray Unwalla,  Felix F Vajdos 2,  Robin A Weinberg,  David C Wood,  Li Xing,  Edouard Zamaratski 1,  Christoph W Zapf,  Yajuan Zhao,  Anna Wilhelmsson 1,  Gabriel Berstein
Affiliations

Affiliations

  • 1 Karo Bio AB (now Karo Pharma AB) , 111 48 Stockholm , Sweden.
  • 2 Medicine Design , Pfizer Inc. , Groton , Connecticut 06340 , United States.
PMID: 30130103 DOI: 10.1021/acs.jmedchem.8b00392
Abstract

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

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