PDBsum entry 4ryc

Hydrolase/hydrolase inhibitor

PDB id: 4ryc

Contents

Protein chains

336 a.a.

Ligands

NAG ×2

3ZK ×2

SO4

DMS

Waters ×222

PDB id:

4ryc

Name:

Hydrolase/hydrolase inhibitor

Title:

Renin in complexed with 4-methoxy-3-(3-methoxypropoxy)-n-{[(3s,4s)-4- {[(4-methylphenyl)sulfonyl]amino}pyrrolidin-3-yl]methyl}-n-(propan-2- yl)benzamide inhibitor

Structure:

Renin. Chain: a, b. Synonym: angiotensinogenase. Engineered: yes

Source:

Homo sapiens. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029

Resolution:

2.45Å R-factor: 0.194 R-free: 0.229

Authors:

N.Ostermann

Key ref:

E.Lorthiois et al. (2015). trans-(3S,4S)-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part I: prime site exploration using an amino linker. Bioorg Med Chem Lett, 25, 1782-1786. PubMed id: 25782742 DOI: 10.1016/j.bmcl.2015.02.039

Date:

15-Dec-14 Release date: 25-Mar-15

Protein chains

P00797  (RENI_HUMAN) -  Renin from Homo sapiens

Seq: 406 a.a.

Struc: 336 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.23.15 - renin.
• Reaction: Cleaves Leu-|- bond in angiotensinogen to generate angiotensin I.

DOI no: 10.1016/j.bmcl.2015.02.039

Bioorg Med Chem Lett 25:1782-1786 (2015)

PubMed id: 25782742

trans-(3S,4S)-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part I: prime site exploration using an amino linker.

E.Lorthiois, F.Cumin, C.Ehrhardt, T.Kosaka, H.Sellner, N.Ostermann, E.Francotte, T.Wagner, J.Maibaum.

ABSTRACT

Recently, we reported on the discovery of (3S,4S)-disubstituted pyrrolidines (e.g., 2) as inhibitors of the human aspartyl protease renin. In our effort to further expand the scope of this novel class of direct renin inhibitors, a new sub-series was designed in which the prime site substituents are linked to the pyrrolidine core by a (3S)-amino functional group. In particular, analogs bearing the corresponding sulfonamide spacer (50, 51 and 54a) demonstrated a pronounced increase in in vitro potency compared to compound 2.