2. Academic Validation
  3. Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists

Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists

  • J Med Chem. 2025 Feb 27;68(4):4818-4828. doi: 10.1021/acs.jmedchem.4c03106.
Brian S Gerstenberger 1,  Ray Unwalla 1,  Kathleen A Farley 2,  Philippe Nuhant 2,  Vincent M Lombardo 2,  Wei Li 3,  Kimberly Crouse 3,  Richard K Frisbie 2,  Eric P Arnold 2,  Mark W Bundesmann 2,  Gary M Chinigo 2,  Andrew Flick 2,  Neelu Kaila 1,  Daniel Lamb 4,  James J Mousseau 2,  Nootaree Niljianskul 2,  Mathieu Rappas 4,  John I Trujillo 2,  Michael L Vazquez 1,  Atli Thorarensen 1,  Mark E Schnute 1
Affiliations

Affiliations

  • 1 Medicine Design, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
  • 2 Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States.
  • 3 Inflammation and Immunology Research, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
  • 4 Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge CB21 6DG, U.K.
PMID: 39960418 DOI: 10.1021/acs.jmedchem.4c03106
Abstract

CCR6 is a Chemokine Receptor that mediates the migration of pathogenic inflammatory leukocytes to sites of inflammation in response to its ligand, CCL20. Herein we report the design of a potent CCR6 Antagonist capable of inhibiting the chemotactic migration of CCR6+ T cells in vitro. Key to this finding was the discovery of a remarkable methyl substituent effect on antagonist potency. A 365-fold improvement in potency was observed for the cis-2-methylcyclohexanamine analogue compared to the unsubstituted cyclohexanamine derivative. Evidence generated through the characterization of conformationally restricted analogues supports the conclusion that the large potency enhancement is the result of the methyl substituent biasing the cyclohexane ring ground state conformation to favor that of the bound ligand and thus decreasing the ligand strain energy.

Figures
Products