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

Add time:08/05/2019    Source:sciencedirect.com

A potent, orally available dual CysLT1 and CysLT2 receptor antagonist with a dicarboxylic acid is described. 4-(3-(Carboxymethyl)-4-{(E)-2-[4-(4-phenoxybutoxy)phenyl]vinyl}-1H-indol-1-yl)butanoic acid (15: ONO-4310321, IC50: CysLT1 = 13 nM, CysLT2 = 25 nM) showed excellent pharmacokinetic profiles (%Frat = 100) compared with our previously reported compound 1 (%Frat = 1.5). In addition, we describe a new rule for dicarboxylic acid derivatives to show good oral bioavailability (%Frat ⩾ 40) in rats (HBDs: ⩽2, C log P: >6.5 and TPSA: <100). Especially, reduction of only one hydrogen-bond donor (HBDs) showed dramatically improved oral bioavailability. This small change of HBDs in dicarboxylic acid derivatives is generally a very effective modification.

We also recommend Trading Suppliers and Manufacturers of 3-Quinolinecarboxylic acid, 1,4-dihydro-4-oxo-8-(phenylsulfonyl)-, ethyl ester (cas 127286-20-8). Pls Click Website Link as below: cas 127286-20-8 suppliers

Prev:Synthesis of 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives as potential antimicrobial agents
Next:On the use of empirically corrected theoretical procedures in preparative chemistry: Synthesis, spectroscopic and theoretical studies on 1,3-bis(trimethylsilyl)benzimidazol-2-one)