2. Academic Validation
  3. Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate

Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate

  • J Med Chem. 2019 Dec 12;62(23):10563-10582. doi: 10.1021/acs.jmedchem.9b01562.
Vidya Ramdas 1,  Rashmi Talwar 1,  Moloy Banerjee 1,  Advait Arun Joshi 1,  Amit Kumar Das 1,  Deepak Sahebrao Walke 1,  Prashant Borhade 1,  Usha Dhayagude 1,  Rajesh Loriya 1,  Ganesh Gote 1,  Apparao Bommakanti 1,  Aruna Sivaram 1,  Gautam Agarwal 1,  Arnab Goswami 1,  Prashant Nigade 1,  Maneesh Mehta 1,  Vinod Patil 1,  Dipak Modi 1,  Hemant Kumar 1,  Sadanand Mallurwar 1,  Amruta Dash 1,  Falguni Modi 1,  Sandip Kuldharan 1,  Pratima Srivastava 1,  Minakshi Singh 1,  Lakshmi Narasimham 1,  Jayasagar Gundu 1,  Sharad Sharma 1,  Rajender Kumar Kamboj 1,  Venkata P Palle 1
Affiliations

Affiliation

  • 1 Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India.
PMID: 31710479 DOI: 10.1021/acs.jmedchem.9b01562
Abstract

The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of Antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.

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