Discovery of Highly Potent Dual CysLT₁ and CysLT₂ Antagonist

Abstract

The benzoxazine derivative, (2S)-4-(3-carboxypropyl)-8-{[4-(4-phenylbutoxy)benzoyl]amino}-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (19, ONO-2050297), was identified as the first potent dual CysLT1 and CysLT2 antagonist with IC50 values of 0.017 μM (CysLT1) and 0.00087 μM (CysLT2), respectively.

Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors

“…To understand the mechanism of ligand selectivity, we performed docking of 18 derivatives of the common 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid scaffold 30,31 with a large spectrum of CysLT 1 R/CysLT 2 R selectivity (Supplementary Table 3). Docking models of the most selective compounds in this structure-activity relationship (SAR) series 30 , cpd 13e (1,800-fold selective for CysLT 1 R) and cpd 15b (200-fold selective for CysLT 2 R), are shown in Fig. 3, alongside with cpd 11a (dual CysLT 1 R/CysLT 2 R), cocrystallized with CysLT 2 R, and pranlukast (4,500-fold selective for CysLT 1 R as shown in Supplementary Fig.…”

Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid

“…These data indicated that it was essential to possess two acidic groups for dual CysLT 1 and CysLT 2 antagonist activities. 19,33 Acylsulfonamide derivative 7 showed equipotent CysLT 2 antagonist activity compared with 1. Interestingly, tetrazole derivative 5 demonstrated significantly potent dual CysLT 1 and CysLT 2 antagonist activities, but it showed quite low permeability.…”

“…The substitution reaction of reported ester analogue 28 19 with NH 3 in ethanol afforded 29. Reductive amination of 29 followed by dehydration afforded nitrile derivative 30.…”

“…19 Compound 1 showed low clearance (CL: 4.7 mL/min/kg) and high metabolic stability in rat liver microsomes (RLM: 100%, 15 min) as shown in Table 1. In spite of high liver microsomal stability, bioavailability of 1 in rats was quite low (%F rat : 1.5) due to low permeability.…”

“…groups is quite acidic according to its calculated pK a value (calculated pK a : 2.5). As shown in our previous report, 19 decreasing the MW and C log P as well as reduction of the number of carboxylic acid groups were attempted, however, it was essential that compounds possess two acidic groups and maintain MW (>500) for highly potent dual CysLT 1 and CysLT 2 antagonist activities. Thus, it was hard to reduce MW, C log P, and remove one of two carboxylic acids without losing of dual antagonist activities.…”