Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2

Abstract

To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.

Figure 1

In vivo cyno PK studies of 1a and 1b.

Figure 2

Structural models of compounds 2c (A) and 2d (B) in CCR5. Unstable waters occupying the hydrophobic pocket between TM3 and EC2 are shown as spheres in (A). (C) WaterMap predicted waters in the hydrophobic pocket between EC2 and TM3 from the CCR2/BMS-687681 crystal structure (RCSB 5T1A).

Figure 3

Compound 2d in the hCCR2 KI mouse TG peritonitis model.

Figure 4

Study the effect of 1a and 2d in EAE model of multiple sclerosis.

Scheme 1

Reagents and conditions. (a) TFA, CH₂Cl₂, rt, 1 h, 93%. (b) Step 1: Me₂CHCHO, MgSO₄, CH₂Cl₂, rt, 1 h; step 2: NCS, MeCN, rt; step 3: NaBH₄, EtOH, rt, 20% for three steps. (c) H₂, Pd(OH)₂, EtOAc, 15 psi, 95%. (d) Step 1: TFA, CH₂Cl₂, rt, 1 h, 93%; step 2: BrCH₂CN, DIEA, MeCN, 40 °C, 16 h; step 3: m-CPBA, CH₂Cl₂, rt, 0.5 h, 55% for 3 three steps. (e) Step 1: NH₂OH·HCl, MeOH, 60 °C, 2 h; step 2: acetone, CH₂Cl₂, rt, 8 h, 58% for two steps. (f) Step 1: MeMgBr, PhH, rt; step 2: CS₂C, MeCN, rt, 30% for two steps.