Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates

  • J Med Chem. 2022 Dec 22;65(24):16234-16251. doi: 10.1021/acs.jmedchem.2c00766.
Mihirbaran Mandal  1 ,  Li Xiao  2 ,  Weidong Pan  1 ,  Giovanna Scapin  2 ,  Guoqing Li  1 ,  Haiqun Tang  1 ,  Shu-Wei Yang  1 ,  Jianping Pan  1 ,  Yuriko Root  1 ,  Reynalda Keh de Jesus  1 ,  Christine Yang  1 ,  Winnie Prosise  2 ,  Priya Dayananth  3 ,  Asra Mirza  4 ,  Alex G Therien  4 ,  Katherine Young  4 ,  Amy Flattery  5 ,  Charles Garlisi  3 ,  Rumin Zhang  3 ,  Donald Chu  3 ,  Payal Sheth  3 ,  Inhou Chu  6 ,  Jin Wu  6 ,  Carrie Markgraf  7 ,  Hai-Young Kim  2 ,  Ronald Painter  3 ,  Todd W Mayhood  3 ,  Edward DiNunzio  3 ,  Daniel F Wyss  2 ,  Alexei V Buevich  8 ,  Thierry Fischmann  2 ,  Alexander Pasternak  1 ,  Shuzhi Dong  1 ,  Jacqueline D Hicks  1 ,  Artjohn Villafania  3 ,  Lianzhu Liang  5 ,  Nicholas Murgolo  4 ,  Todd Black  4 ,  William K Hagmann  1 ,  Jim Tata  1 ,  Emma R Parmee  1 ,  Ann E Weber  1 ,  Jing Su  1 ,  Haifeng Tang  1
Affiliations
  • 1. Medicinal Chemistry, Merck & Co., Inc., Kenilworth, New Jersey07033, United States.
  • 2. Computational and Structural Chemistry, Merck & Co., Inc., Kenilworth, New Jersey07033, United States.
  • 3. In-vitro biology, Merck & Co., Inc., Kenilworth, New Jersey07033, United States.
  • 4. Antibacterial/antifungal, Merck & Co., Inc., Kenilworth, New Jersey07033, United States.
  • 5. In vivo biology, Merck & Co., Inc., Kenilworth, New Jersey07033, United States.
  • 6. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey07033, United States.
  • 7. Nonclinical Drug Safety, Merck & Co., Inc., Kenilworth, New Jersey07033, United States.
  • 8. Analytical Research and Development, Merck & Co., Inc., Kenilworth, New Jersey07033, United States.
PMID: 36475645 DOI: 10.1021/acs.jmedchem.2c00766
Abstract

With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against Bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the Bacterial burden in a murine Infection model and became the lead for the invention of MBLI clinical candidates.

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