Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672

Abstract

We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.

Figure 1

Compounds with similar CCR2 binding affinity but strikingly different overall profiles.

Figure 2

Shown is a plot of cLog P vs PAMPA (normalized to reference standard 1) for a series of analogs from the trisubstituted cyclohexyl series. All of these compounds are analogs of 1, 5, and 6 in that they contain the N-isopropyl, N-methyl-amine motif, the γ-lactam linker, and the quinazoline capping group.

Scheme 1. Synthesis of BMS-741672 (7)

Reagents and conditions: (a) 1 atm H₂, Pd/C, EtOAc; (b) Cbz-Met-OH, TBTU, iPr₂NEt, MeCN; (c) MeI, 48 h; (d) Cs₂CO₃, DMSO; (e) LiOH, THF/H₂O; (f) EDC, HOBt, CH₂Cl₂, then NH₃; (g) PhI(OAc)₂, MeCN/H₂O, then Ac₂O, iPr₂NEt; (h) TFA, CH₂Cl₂; (i) acetone, NaBH₃CN, MeOH; (j) CH₂O, NaB(OAc)₃H, CH₂Cl₂; (k) 1 atm H₂, Pd/C, MeOH; (l) 4-Cl,6-CF₃-quinazoline, iPr₂NEt, iPrOH.

Figure 3

X-ray crystal structures of compounds 1, 6, and 7. (A) The bis-benzenesulfonic acid (omitted for clarity) salt of 7 (orange) exists in the chair configuration with γ-lactam disposed axially. The free base of 7 (blue) exists in the chair configuration with the γ-lactam disposed equatorially. (B) Hydrogen-bonding network in the 7 free-base crystal structure. (C) The X-ray structures of the free-base of 1 (red) and TFA (omitted for clarity) salt of 6 (orange) overlaid with the CCR2-bound conformation of the protonated form of 1 (blue) extracted from the 1/CCR2 complex crystal structure (PDB ID: 5T1A). All exist in the LADE chair conformation. (D) Hydrogen-bonding network in the 6 TFA salt crystal structure.

Figure 4

Working model for the equilibrium populations of acetamide 7 in both high-dielectric aqueous and low-dielectric lipid environments. Percentages on the horizontal arrows are Boltzmann populations calculated from the relative ab initio conformational energies, denoted beneath each structure. The Boltzmann populations on the vertical arrows are calculated using the Henderson–Hasselbalch equation using an amine pK_a of 9.5 and buffer pH of 7.3.