PDBsum entry 3q5h

Hydrolase/hydrolase inhibitor

PDB id: 3q5h

Contents

Protein chain

337 a.a.

Ligands

NAG-NAG

RX6 ×2

Metals

_CL ×6

Waters ×168

PDB id:

3q5h

Name:

Hydrolase/hydrolase inhibitor

Title:

Clinically useful alkyl amine renin inhibitors

Structure:

Renin. Chain: a, b. Fragment: unp residues 67-406. Synonym: angiotensinogenase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ren, renin. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek 293.

Resolution:

2.16Å R-factor: 0.226 R-free: 0.268

Authors:

Z.Wu,B.M.Mckeever

Key ref:

L.Jia et al. (2011). Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility. Acs Med Chem Lett, 2, 747-751. PubMed id: 24900262 DOI: 10.1021/ml200137x

Date:

28-Dec-10 Release date: 30-Nov-11

Protein chains

P00797  (RENI_HUMAN) -  Renin from Homo sapiens

Seq: 406 a.a.

Struc: 337 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: 10.1021/ml200137x

Acs Med Chem Lett 2:747-751 (2011)

PubMed id: 24900262

Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.

L.Jia, R.D.Simpson, J.Yuan, Z.Xu, W.Zhao, S.Cacatian, C.M.Tice, J.Guo, A.Ishchenko, S.B.Singh, Z.Wu, B.M.McKeever, Y.Bukhtiyarov, J.A.Johnson, C.P.Doe, R.K.Harrison, G.M.McGeehan, L.W.Dillard, J.J.Baldwin, D.A.Claremon.

ABSTRACT

Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.