Structure‐based discovery of (S)‐2‐amino‐6‐(4‐fluorobenzyl)‐5, 6, 11, 11a‐tetrahydro‐1H‐imidazo[1′, 5′:1, 6]pyrido[3, 4‐b]indole‐1, 3(2H)‐dione as low nanomolar, orally bioavailable autotaxin inhibitor. (3rd January 2022)

• Record Type: Journal Article
• Authors: Roy, Ashis; Sarkar, Tonmoy; Datta, Sebak; Maiti, Arup; Chakrabarti, Monali; Mondal, Trisha; Mondal, Chaitali; Banerjee, Apurba; Roy, Subhasis; Mukherjee, Soumen; Muley, Pragati; Chakraborty, Sabyasachi; Banerjee, Manish; Kundu, Mrinalkanti; Roy, Kuldeep K.
• Is Part Of: Chemical biology & drug design. Volume 99:Number 3(2022)
• Page Start: 496
• Page End: 503
• Publication Date: 2022-01-03
• Subjects: ADME -- aminohydantoin -- autotaxin -- docking -- drug design -- in vitro -- PK; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.14017
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure‐based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1 . During the molecular docking and scoring studies within the ATX enzyme (PDB‐ID: 4ZGA), the S ‐enantiomer (Gscore = −13.168 kcal/mol) of the bound ligand PAT‐494 scored better than its R ‐enantiomer (Gscore = −9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT‐494 . Accordingly, the docking‐based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L‐tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME‐PK studies divulged compound 1 as non‐cytotoxic (19.02% cell growth inhibition at 20 μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint = 15.6 μl/min/mg; T 1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments. Abstract : Intervention in the ATX‐LPA signaling cascade has been a promising strategy to treat various diseases and led to the discovery of novel molecular entities some of which progressed to different stages in clinical trials albeit varied success. We herein divulge structure‐based discovery of a polycyclic aminohydantoin derivative 1 as potent, non‐cytotoxic, metabolically stable, and orally bioavailable autotaxin inhibitor.