Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability

Abstract

The chemokine receptors CXCR1 and CXCR2 are important pharmaceutical targets due to their key roles in inflammatory diseases and cancer progression. We have previously identified 2-[5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanylmethyl]-phenylboronic acid (SX-517) and 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide (SX-576) as potent non-competitive boronic acid-containing CXCR1/2 antagonists. Herein we report the synthesis and evaluation of aminopyridine and aminopyrimidine analogs of SX-517 and SX-576, identifying (2-{(benzyl)[(5-boronic acid-2-pyridyl)methyl]amino}-5-pyrimidinyl)(4-fluorophenylamino)formaldehyde as a potent chemokine antagonist with improved aqueous solubility and oral bioavailability.

Keywords: Antagonist; Asthma; COPD; CXCR1; CXCR2.

Figure 1

Chemokine antagonists

Figure 2

Ozone rat model of pulmonary inflammation. ***p < 0.001, ****p < 0.0001, t-test of 6 or 7 vs. positive control and 6 vs. 7.

Scheme 1

Reagents and conditions: (i) primary or secondary amine, DIPEA, anh. DMF or NMP, 120-160°C, 16-72 hours; (ii) PdCl₂(dppf), bis(pinacolato)diboron, potassium acetate, anh. DMF, 80°C, 3-6 hours; (iii) KHF₂, then TMS-Cl/H₂O or HCl/dioxane or aq. formic acid; (iv) primary or secondary amine, triethylamine, anh. NMP, RT, 16-72 hours.