Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

Dhilli Rao Gorja; Soumita Mukherjee; Chandana Lakshmi T. Meda; Girdhar Singh Deora; K. Lalith Kumar; Ankit Jain; Girish H. Chaudhari; Keerthana S. Chennubhotla; Rakesh K. Banote; Pushkar Kulkarni; Kishore V. L. Parsa; K. Mukkanti; Manojit Pal

doi:10.1039/C3OB27424A

Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors†

Dhilli Rao Gorja,^ab Soumita Mukherjee,^a Chandana Lakshmi T. Meda,^a Girdhar Singh Deora,^a K. Lalith Kumar,^a Ankit Jain,^ac Girish H. Chaudhari,^ac Keerthana S. Chennubhotla,^ac Rakesh K. Banote,^ac Pushkar Kulkarni,^ac Kishore V. L. Parsa,*^a K. Mukkanti^b and Manojit Pal*^a

Author affiliations

* Corresponding authors

^a Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India
E-mail: manojitpal@rediffmail.com

^b Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072, India

^c Zephase Therapeutics Pvt. Ltd (An incubated company at the Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India

Abstract

A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is described via the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC₅₀ 1.1 μM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed significant inhibition of TNF-α and no major toxicities in cell lines and a zebrafish embryo model except the teratogenic effects to be re-assessed in rodents.

Organic & Biomolecular Chemistry

Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors†

Abstract

Supplementary files

Article information

Download Citation

Permissions

Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

Social activity

Search articles by author

Spotlight

Advertisements