172595-66-3

Upstream product

• 1075-35-0 5-chloro-2-methylindole 
• 96-32-2 bromoacetic acid methyl ester 
• 41052-75-9 o-chlorophenylhydrazine hydrochloride 

Downstream Products

• 872674-61-8 methyl [5-chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]acetate 
• 19017-52-8 2-(5-chloro-2-methyl-1H-indol-3-yl)acetic acid 
• 1297284-50-4 methyl 2-(3-((3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)-5-chloro-2-methyl-1H-indol-1-yl)acetate 
• 1297284-49-1 2-benzyl-4-((5-chloro-2-methyl-1H-indol-3-yl)methyl)-phthalazin-1(2H)-one 
• 1297284-47-9 2-(2-(5-chloro-2-methyl-1H-indol-3-yl)acetyl)benzoic acid 
• 1297276-86-8 2-(3-((3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-5-chloro-2-methyl-1H-indol-1-yl)acetic acid 
• 872674-63-0 methyl 4-[[[[5-chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]acetyl]amino]methyl]benzoate 
• 872674-62-9 [5-chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]acetic acid 

Relevant academic research and scientific papers

Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins (KLKs). Many KLKs are investigated as potential biomarkers for cancer as well as therapeutic drug targets for a number of pathologies. KLK6, in particular, has been implicated in neurodegenerative diseases and cancer, but target validation has been hampered by a lack of selective inhibitors. This work introduces a class of depsipeptidic KLK6 inhibitors, discovered via high-throughput screening, which were found to function as substrate mimics that transiently acylate the catalytic serine of KLK6. Detailed structure-activity relationship studies, aided by in silico modeling, uncovered strict structural requirements for potency, stability, and acyl-enzyme complex half-life. An optimized scaffold, DKFZ-251, demonstrated good selectivity for KLK6 compared to other KLKs, and on-target activity in a cellular assay. Moreover, DKFZ-633, an inhibitor-derived activity-based probe, could be used to pull down active endogenous KLK6.

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

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.

INDOLE BASED RECEPTOR CRTH2 ANTAGONISTS

Disclosed are compounds of Formula (I): which are useful as antagonists of the CRTH2 receptors. Pharmaceutical compositions containing compounds of Formula (I) and the use of compounds of Formula (I) to treat diseases or disorders that are responsive to inhibition of the binding of endogenous ligands to the CRTH2 receptor are also disclosed. Methods for preparing and using these compounds are further described.

Inhibition of cytosolic phospholipase A2α: Hit to lead optimization

Compound 1 was previously reported to be a potent inhibitor of cPLA 2α in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC50 of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzole acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-γ- linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA2α inhibition. The IC50s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA2α and represent well-validated starting points for further optimization.

Indole derivatives useful to treat estrogen-related neoplasms and disorders

The present invention relates to novel indole derivatives useful in down-regulating estrogen receptor expression. Also included are methods for the treatment of neoplasms or of controlling the growth of a neoplasm in a patient afflicted with a neoplastic disease, especially estrogen-dependent neoplasms such as those associated with breast, ovarian and cervical tissue. Another embodiment of the present invention is a method of prophylactically treating a patient at risk of developing a neoplastic disease state. Also provided is a method for treating autoimmune diseases. Also included are pharmaceutical compositions of the novel indole derivatives.