PDBsum entry 5exn

Hydrolase/hydrolase inhibitor

PDB id: 5exn

Contents

Protein chain

237 a.a.

Ligands

NAG

5SU

Waters ×221

PDB id:

5exn

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor xia (c500s [c122s]) in complex with the inhibitor methyl ~{n}- [4-[2-[(1~{s})-1-[[(~{e})-3-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl) phenyl]prop-2-enoyl]amino]-2-phenyl-ethyl]pyridin-4- yl]phenyl]carbamate

Structure:

Coagulation factor xia light chain. Chain: a. Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: komagataella pastoris. Expression_system_taxid: 4922.

Resolution:

1.49Å R-factor: 0.171 R-free: 0.195

Authors:

S.Sheriff

Key ref:

J.R.Corte et al. (2016). Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group. Bioorg Med Chem Lett, 24, 2257-2272. PubMed id: 27073051 DOI: 10.1016/j.bmc.2016.03.062

Date:

23-Nov-15 Release date: 13-Apr-16

Protein chain

P03951  (FA11_HUMAN) -  Coagulation factor XI from Homo sapiens

Seq: 625 a.a.

Struc: 237 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.21.27 - coagulation factor XIa.
• Reaction: Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.

DOI no: 10.1016/j.bmc.2016.03.062

Bioorg Med Chem Lett 24:2257-2272 (2016)

PubMed id: 27073051

Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group.

J.R.Corte, T.Fang, D.J.Pinto, M.J.Orwat, A.R.Rendina, J.M.Luettgen, K.A.Rossi, A.Wei, V.Ramamurthy, J.E.Myers, S.Sheriff, R.Narayanan, T.W.Harper, J.J.Zheng, Y.X.Li, D.A.Seiffert, R.R.Wexler, M.L.Quan.

ABSTRACT

Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.