Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids

Abstract

Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to idiosynchratic toxicity in humans. In this communication, we describe a new series of compounds that lack the carboxylic acid moiety. Compounds with high affinity (K i < 10 nM) for the receptor have been identified. Subsequent optimization succeeded in reducing the high metabolic clearance of the first compounds in human and rat liver microsomes. At the same time, inhibition of the CYP isoforms was optimized, giving rise to stable compounds with an acceptable CYP inhibition profile (IC 50 CYP2C9 and 2C19 > 1 μM). Taken together, these data show that compounds devoid of carboxylic acid groups could represent an interesting alternative to current CRTH2 antagonists in development.

Acyl Cyanides as Bifunctional Reagent: Application in Copper-Catalyzed Cyanoamidation and Cyanoesterification Reaction

“…13 N-(3-Cyano-5-fluorophenyl)benzamide (3e). 25 Yellow solid (35 mg, 73%); mp 145−146 °C; R f = 0.44 (petroleum ether/ethyl acetate = 4:1); 1 H NMR (400 MHz, CDCl 3 ): δ = 8.37 (s, 1H), 7.93−7.82 (m, 3H), 7.70 (s, 1H), 7.61−7.54 (m, 1H), 7.47 (dd, J = 10.5, 4.7 Hz, 2H), 7.10 (ddd, J = 7.6, 2.4, 1.3 Hz, 1H). 13 N-(4-Cyano-2-nitrophenyl)benzamide (3g).…”

Diazine Indole Acetic Acids as Potent, Selective, and Orally Bioavailable Antagonists of Chemoattractant Receptor Homologous Molecule Expressed on Th2 Cells (CRTH2) for the Treatment of Allergic Inflammatory Diseases

“…General procedure A was followed starting with 7-(methylsulfonyl)-5-fluoro-2-methyl-1 H -indole, which was prepared from 4-fluoro-2-(methylsulfonyl)aniline according to Scheme . , Y = Me. Solid (overall yield, 24%).…”

“…Scheme a was followed starting with 5,7-difluoro-2-methyl-1 H -indole, which was prepared from 2,4-difluoroaniline according to Scheme . , Solid (overall yield, 48%). 1 H NMR (400 MHz, MeOD) δ ppm 2.22 (s, 3 H), 3.86 (s, 2 H), 4.84 (s, 2 H), 5.24 (s, 2 H), 6.49–6.56 (m, 1 H), 6.70–6.86 (m, 3 H), 6.74 (d, J = 9.60 Hz, 1 H), 7.11 (d, J = 9.60 Hz, 1 H), 7.18–7.26 (m, 1H).…”

“…Successful clinical results in the past few years have stimulated interest in discovering potent, selective, and orally active CRTH2 antagonists for the treatment of asthma. Arylacetic acid is a common motif for a large number of CRTH2 antagonists reported in the literature. , Our starting point was diazine indole acetic acids . A cAMP cell based competitive immunoassay (hCRTH2 FRET) using Eu 3+ cryptate labeled anti-cAMP and d2-labeled cAMP was used as a primary in vitro screen.…”

facile, highly efficient and novel method for synthesis of 5-substituted 1H-tetrazoles catalysed by copper(I) chloride

“…It was recently reported that nanocrystalline ZnO (Lakshmi Kantam et al, 2005) (Crosignani et al, 2011;Jin et al, 2008) and nano CuO (Yapuri et al, 2013) were used in the synthesis of tetrazole compounds as various homogeneous and heterogeneous catalysts. In addition, metalmodified montmorillonites and zeolite were widely reported, and many metals such as Cu, Mn, Fe, Mo, Al and Co (Clark et al, 1997;Varma, 2002;Carriazo et al, 2003;Shinde et al, 2004;Yin & Shi, 2005;Ben Achma et al, 2008;Rama et al, 2011) were commonly used in improving the catalytic abilities of montmorillonites.…”