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  • The pharmacokinetics properties of compound were evaluated


    The pharmacokinetics properties of compound were evaluated in male Sprague Dawley rats following IV (0.7mg/kg) and oral (2.0mg/kg) dosing. The total body clearance and the terminal half-life were 0.73 L/h/kg and 5.1h, respectively. After oral administration the compound showed good bioavailability (38%) following administration of a solution formulation (1mL/kg; 10% ethanol:90% PEG400). In summary, we have discovered and optimized a series of tetrahydroquinoline derivatives as potent CRTH2 antagonists with selectivity over DP. Furthermore, we have identified compound as a potent CRTH2 antagonist with good pharmacokinetic properties rendering it a useful tool compound for in vivo studies of CRTH2 functions.
    CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells, also known as DP) and DP (prostanoid D receptor, also known as DP) are two G-protein coupled receptors activated by prostaglandin D (PGD). Numerous studies using DP and CRTH2 antagonists, combined with genetic analysis, support the view that these receptors play a pivotal role in mediating allergic diseases., , Therefore, there have been a lot of research and development activities for DP and CRTH2 antagonists, especially for CRTH2 antagonists., , , , , , , , , , , , , , , We believe that blockade of both receptors may prove more beneficial in alleviating allergic diseases triggered by PGD than inhibiting either one; therefore we have been interested in identifying potent CRTH2/DP dual inhibitors, such as AMG 009 and AMG 853 ()., AMG 009, our first-generation dual antagonist, is more potent against CRTH2 than DP. It displaced H-PGD from the CRTH2 receptors expressed on HEK 293 Genomic DNA Isolation Kit with IC of 3nM in buffer and 21nM in the presence of 50% plasma. It displaced H-PGD from the DP receptors expressed on HEK 293 cells with IC of 12nM in buffer and 280nM in the presence of 50% plasma. AMG 853, our second-generation dual antagonist, is a more balanced dual antagonist. Here we report our efforts in identifying other more potent and balanced dual antagonists. Most of the phenylacetic acid derivatives in this Letter (–) were prepared using the same route reported in our early communication. Sulfoxide and sulfone were obtained from the oxidation of sulfide using 3-chloroperoxybenzoic acid. Compounds in were synthesized through derivatizing the benzoic acid intermediate, a product of step (a) in . Synthesis of compound is illustrated in as an example. The benzoic acid intermediate was converted into the acid chloride, which was treated with 1-pentyne to afford the acetylenic ketone (step b, ii). The acetylenic ketone was converted into the pyrazole using hydrazine (step c). Reduction of the nitro group followed by treatment with sulfonyl chloride in pyridine afforded compound after the final ester hydrolysis. Optimization of this series of phenylacetic acid derivatives is mainly divided into four areas: phenylacetic acid, bisaryl ether linker, sulfonamide and amide (). A portion of the structure–activity relationship (SAR) has been reported., , Here we discuss the SAR that led to the identification of more balanced dual antagonists and present a more complete picture of the SAR of this chemical series. The sulfonamide was important for the DP activity: no potent dual antagonists were identified through the modification of this functional group. Multiple modifications of the phenylacetic acid moiety have been reported, such as bioisoteric replacements of the carboxylic acid, and the substitutions on the phenyl ring and at the α-position of the phenylacetic acid., shows another modification in the area of the phenylacetic acid, the heterocyclic replacements of the phenyl ring. Most of the heterocyclic replacements resulted in a reduction in potency, especially for DP. The benzofuran derivative () was an exception. It maintained the CRTH2 potency and slightly increased the DP potency in buffer. However, the improved DP binding potency in buffer was not maintained in the presence of plasma, as compared to that of AMG 009 (data not shown).