2. Academic Validation
  3. Design of Novel Mercapto-3-phenylpropanoyl Dipeptides as Dual Angiotensin-Converting Enzyme C-Domain-Selective/Neprilysin Inhibitors

Design of Novel Mercapto-3-phenylpropanoyl Dipeptides as Dual Angiotensin-Converting Enzyme C-Domain-Selective/Neprilysin Inhibitors

  • J Med Chem. 2025 Apr 10;68(7):7720-7736. doi: 10.1021/acs.jmedchem.5c00329.
Gyles E Cozier 1,  Lauren B Coulson 2 3,  Charles J Eyermann 4,  Gregory S Basarab 4,  Sylva L Schwager 2 3,  Kelly Chibale 2 4 5 6,  Edward D Sturrock 2 3,  K Ravi Acharya 1
Affiliations

Affiliations

  • 1 Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
  • 2 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.
  • 3 Department of Integrative Biomedical Sciences, University of Cape Town, Observatory 7925, South Africa.
  • 4 Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa.
  • 5 Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 6 South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
PMID: 40168649 DOI: 10.1021/acs.jmedchem.5c00329
Abstract

Dual angiotensin-converting enzyme (ACE) and Neprilysin (NEP) inhibitors such as omapatrilat showed promise as potent treatments for hypertension but produced adverse effects due to their high affinity for both domains of ACE (nACE and cACE). This led to the search for compounds that retained NEP potency but selectively inhibit cACE, leaving nACE active to degrade Other peptides such as bradykinin. Lisinopril-tryptophan (LisW) has previously been reported to have cACE selectivity. Three mercapto-3-phenylpropanoyl inhibitors were synthesized, combining features of omapatrilat and LisW to probe structural characteristics required for potent dual cACE/NEP inhibition. We report the synthesis of these inhibitors, enzyme inhibition data, and high-resolution crystal structures in complex with nACE and cACE. This provides valuable insight into factors driving potency and selectivity and shows that the mercapto-3-phenylpropanoyl backbone is significantly better for NEP potency than a P1 carboxylate. Future chemistry efforts could be directed at identifying alternative chemotypes for optimization of cACE/NEP inhibitors.

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