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

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

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z