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

Abstract

New classes of CRTH2 antagonists, the pyridazine linker containing indole acetic acids, are described. The initial hit 1 had good potency but poor permeability, metabolic stability, and PK. Initial optimization led to compounds of type 2 with low oxidative metabolism but poor oral bioavailability. Poor permeability was identified as a liability for these compounds. Addition of a linker between the indole and diazine moieties afforded a series with good potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. 32 was identified as the development track candidate. It was potent in cell based, binding, and whole blood assays and exhibited good PK profile. It was efficacious in mouse models of contact hypersensitivity (1 mg/kg b.i.d.) and house dust (20 mg/kg q.d.) when dosed orally. In sheep asthma, administration at 1 mg/kg iv completely blocked the LAR and AHR and attenuated the EAR phase.

Synthesis of novel phthalazine derivatives as pharmacological activities

“…And in the recent years, they got interest because of their magnificent pharmacological and therapeutic properties, and phthalazines linked amino acid derivatives as a new class of promising antimicrobial, antitumor, anihypertensive, antidiabetic,anti‐inflammatory, and vesarelaxant activities . The integration of amino acid residues in various oxygen‐,nitrogen‐, and sulfur‐containing heterocycles sometimes enhances the biological profile manifold over that of its parent nucleus . According to these observations and in continuation of our work on synthesis heterocycles of pharmacological interest, there was an interest in synthesizing new molecules involving phthalazine and amino acid moieties in a single molecular framework that possibly have antitumor, antioxidant, and DNA agents.…”

A New Method for the Preparation of Intermediates for 2,6‐Substituted Anthrapyridazones

“…In the second step, the alkylation of 3 required us to try a variety of electrophilic reagents as well as different solvents and temperature conditions in order to find the most efficient method. First of all, literature procedures for the alkylation of pyridazinones were tested. However, the attempts to directly transfer the published reaction conditions to the alkylation of 3 by 2‐(dimethylamino)ethyl chloride hydrochloride ( 4a ) failed.…”

Copper‐Catalyzed Aerobic Dehydrogenation of C–C to C=C Bonds in the Synthesis of Pyridazinones

“…For instance, N (2)‐substituted pyridazinone with a heterocycle such as benzothiazole was prepared with respectable yield (68 %; Table 3, entry 5). Recently, a structurally similar compound based on N (2)‐benzylated pyridazinone containing fluorine has been developed for the treatment of allergic inflammatory diseases, which exhibits potent, selective and orally bioavailable antagonists of a chemoattractant receptor homologous molecule expressed on Th2 cells 23. Herein, a series of similar substrates were used in the reaction and excellent yields were obtained, which represents a significant advance of this catalytic system in terms of economy and practicality in pharmaceutical synthesis (Table 3, entries 11–20).…”