Design, synthesis, and biological evaluation of 2‐substituted‐2, 3, 4, 9‐tetrahydrospiro‐β‐carboline‐3‐carboxylic acid derivatives as first‐in‐class mast cell stabilizers. Issue 5 (12th April 2018)

• Record Type: Journal Article
• Authors: Singh, Jatinder; Shah, Ramanpreet; Singh, Dhandeep; Jaggi, Amteshwar S.; Singh, Nirmal
• Is Part Of: Archiv der Pharmazie. Volume 351:Issue 5(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-04-12
• Subjects: β‐carboline -- compound 48/80 -- geminal and vicinal coupling -- mast cell stabilizers -- Pictet–Spengler reaction; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201800019
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: Mast cell degranulation plays a momentous role in myriad diseases like asthma, eczema, allergic rhinitis, and conjunctivitis as well as anaphylactic shock; hence, there is an unmet need for developing new mast cells stabilizers. The reported mast cell stabilizers have a heterocyclic moiety and an acidic group. Furthermore, the role of tryptophan in suppression of mast cell activation is established. Hence, we prepared constrained analogs of tryptophan, which are derivatives of 2, 3, 4, 9‐tetrahydrospiro‐β‐carboline‐3‐carboxylic acid, and evaluated them for ex vivo inhibition of compound 48/80‐induced mast degranulation activity. By comparing IC50 (μM) values with that of the standard drug sodium cromoglycate (IC50 = 0.489 ± 0.003 μM), compounds with bulky groups like heptyl (compound 9 ; IC50 = 0.389 ± 0.015 μM) and octyl (compound 10 ; IC50 = 0.354 ± 0.023 μM) were found to be of similar potency as sodium cromoglycate. Furthermore, the polar group‐containing compounds like the chloropropyl (compound 16 ; IC50 = 0.382 ± 0.083 μM) and benzoyl derivative (compound 14 ; IC50 = 00.469 ± 0.032 μM) were also found to be of similar potency as sodium cromoglycate. This is a seminal study of spiro‐β‐carboline mast cell stabilization having a wider scope in mast cell research; yet, the mechanism of action remains elusive. Abstract : Due to the established role of tryptophan in suppression of mast cell activation, constrained analogs of tryptophan we prepared and evaluated for their inhibitory activity on compound 48/80‐induced mast degranulation. Compounds with bulky groups (heptyl and octyl) were found to be of similar potency as cromolyn, and polar group‐containing compounds (chloropropyl and benzoyl derivatives) were found to be as active as sodium cromoglycate.