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

Also in #JMedChemASAP - anyone can have a “Magic Methyl” but what about a SUPER Methyl!! Oh and a squareamide too…
#ChemSky #PfizerChemistry

Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 ...

A cool spirocycle will always make me have a look at a paper and this one from #Novartis in #JMedChemASAP has that look - spiropiperidine with an “ortho” amide linkage. It’s cool stuff, but it’s the neat reaction in the synthetic scheme tag at caught my eye…1/2