Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy

  • Bioorg Med Chem Lett. 2021 Sep 1:47:128202. doi: 10.1016/j.bmcl.2021.128202.
Abhisek Banerjee  1 ,  Ranganadh Velagaleti  1 ,  Sandip Patil  1 ,  Mahesh Pawar  1 ,  Pravin Yadav  1 ,  Pradip Kadam  1 ,  Mohammad Mohsin Qadri  1 ,  Samitabh Chakraborti  2 ,  Jagmohan S Saini  3 ,  Dayanidhi B Behera  4 ,  Keya Karanjai  1 ,  Pravin S Iyer  5 ,  Laxmikant A Gharat  1 ,  Sanjib Das  6
Affiliations
  • 1. Medicinal Chemistry Division, Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.
  • 2. Pharmacology Division, Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.
  • 3. Computational Chemistry, Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.
  • 4. Drug Metabolism and Pharmacokinetics, Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.
  • 5. Medicinal Chemistry Division, Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.; Pharmacology Division, Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.; Computational Chemistry, Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.; Drug Metabolism and Pharmacokinetics, Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.
  • 6. Medicinal Chemistry Division, Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.. Electronic address: [email protected].
PMID: 34139325 DOI: 10.1016/j.bmcl.2021.128202
Abstract

Cathepsin C plays a key role in the activation of several degradative Enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C Inhibitor 3p, free of aortic binding liability.

Keywords
Amidoacetonitrile-based Cathepsin C inhibitors; Aortic binding; Catalytic cysteine residue (Cys234); Chronic Obstructive Pulmonary Disease (COPD); Coronavirus SARS-CoV-2; α-Amino acid based scaffold.
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