105399-06-2

Upstream product

• 4792-67-0 5-chloro-indole-2-carboxylic acid ethyl ester 
• 98-88-4 benzoyl chloride 
• 65-85-0 benzoic acid 

Downstream Products

• 1374964-63-2 1-tert-butyl 2-ethyl 3-benzoyl-5-chloro-1H-indole-1,2-dicarboxylate 
• 26868-66-6 ethyl 3-benzyl-5-chloro-1H-indole-2-carboxylate 

Relevant academic research and scientific papers

Novel indole based NNRTIs with improved potency against wild type and resistant HIV

The human immunodeficiency virus (HIV) pandemic remains a significant problem, especially in developing nations where the social and economic impacts are severe. Until a cure or vaccine for the disease is found, a constant supply of new compounds to fill the drug development pipeline is a requirement, given the tendency for the virus to rapidly develop resistance to current therapies. Here we disclose our efforts to improve upon the efficacy of cyclopropyl-indole derivatives developed as NNRTIs in our laboratories. To this end, modifications to the functionality occupying the small Val179 pocket have resulted in nearly two orders of magnitude increase in potency.

Novel indole sulfides as potent HIV-1 NNRTIs

In a previous communication we described a series of indole based NNRTIs which were potent inhibitors of HIV replication, both for the wild type and K103N strains of the virus. However, the methyl ether functionality on these compounds, which was crucial for potency, was susceptible to acid promoted indole assisted SN1 substitution. This particular problem did not bode well for an orally bioavailable drug. Here we describe bioisosteric replacement of this problematic functional group, leading to a series of compounds which are potent inhibitors of HIV replication, and are acid stable.

SUBSTITUTED INDOLES AND THEIR USE AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Compounds of Formula I or pharmaceutically acceptable salts thereof are claimed, wherein R1 is an ester, amide or a heterocycle; R2 is C or N; R3 is a methoxy or ethoxy group, an alkyl group or a heterocyclic group; R4 is a substituted or unsubstituted phenyl or heteroaromatic group; and R5 is a halide or a nitrile. The use of these compounds as non-nucleoside reverse transcriptase inhibitors (NNRTIs) for inhibiting or treating HIV infection or AIDS is also described.

BETA-ARRESTIN-BIASED CANNABINOID CB1 RECEPTOR AGONISTS AND METHODS FOR MAKING AND USING THEM

The present invention provides compounds having a CB1 receptor-binding moiety and a directing moiety. In related aspects, the invention provides pharmaceutical compositions containing compounds of the invention, methods for inhibiting a pathway modulated in part by the CB1 receptor activity, and methods for treating a condition or disorder mediated in part by CB1 receptor activity. In certain embodiments, the compounds are compounds of Formula (I). Methods of preparing compounds of Formula (I) are also described. In another aspect, the invention provides methods of identifying a selective agonist of the beta-arrestin pathway over the G-protein pathway.

Structure-activity relationship study of indole-2-carboxamides identifies a potent allosteric modulator for the cannabinoid receptor 1 (CB1)

The cannabinoid CB1 receptor is involved in complex physiological functions. The discovery of CB1 allosteric modulators generates new opportunities for drug discovery targeting the pharmacologically important CB1 receptor. 5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2- carboxamide (ORG27569; 1) represents a new class of indole-2-carboxamides that exhibit allostery of CB1. To better understand the SAR, a group of indole-2-carboxamide analogues were synthesized and assessed for allostery of the CB1 receptor. We found that within the structure of indole-2-carboxamides, the presence of the indole ring is preferred for maintaining the modulator's high binding affinity for the allosteric site but not for generating allostery on the orthosteric site. However, the C3 substituents of the indole-2-carboxamides significantly impact the allostery of the ligand. A robust CB1 allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-pentyl-1H- indole-2-carboxamide (11j) was identified. It showed an equilibrium dissociation constant (KB) of 167.3 nM with a markedly high binding cooperativity factor (α = 16.55) and potent antagonism of agonist-induced GTPγS binding.

Novel cyclopropyl-indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors

The HIV pandemic represents one of the most serious diseases to face mankind in both a social and economic context, with many developing nations being the worst afflicted. Due to ongoing resistance issues associated with the disease, the design and synthesis of anti-HIV agents presents a constant challenge for medicinal chemists. Utilizing molecular modeling, we have designed a series of novel cyclopropyl indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors and carried out their preparation. These compounds facilitate a double hydrogen bonding interaction to Lys101 and efficiently occupy the hydrophobic pockets in the regions of Tyr181/188 and Val179. Several of these compounds inhibited HIV replication as effectively as nevirapine when tested in a phenotypic assay.