TY - JOUR
T1 - InCl
3
mediated heteroarylation of indoles and their derivatization via C[sbnd]H activation strategy
T2 - Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis
AU - Sunke, Rajnikanth
AU - Bankala, Ramudu
AU - Thirupataiah, B.
AU - Ramarao, E. V.V.Shivaji
AU - Kumar, Jetta Sandeep
AU - Doss, Hari Maduri
AU - Medishetti, Raghavender
AU - Kulkarni, Pushkar
AU - Kapavarapu, Ravi Kumar
AU - Rasool, Mahaboobkhan
AU - Mudgal, Jayesh
AU - Mathew, Jessy E.
AU - Shenoy, Gautham G.
AU - Parsa, Kishore V.L.
AU - Pal, Manojit
N1 - Publisher Copyright:
© 2019 Elsevier Masson SAS
PY - 2019/7/15
Y1 - 2019/7/15
N2 -
A new class of PDE4 inhibitors were designed and synthesized via the InCl
3
mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed C[sbnd]H activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC
50
= 0.39 ± 0.13 μM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively)showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE)model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints)as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity)in Zebrafish.
AB -
A new class of PDE4 inhibitors were designed and synthesized via the InCl
3
mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed C[sbnd]H activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC
50
= 0.39 ± 0.13 μM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively)showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE)model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints)as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity)in Zebrafish.
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U2 - 10.1016/j.ejmech.2019.04.020
DO - 10.1016/j.ejmech.2019.04.020
M3 - Article
AN - SCOPUS:85064738103
SN - 0223-5234
VL - 174
SP - 198
EP - 215
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -