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PDBsum entry 4lko
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PDB id:
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Hydrolase
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Title:
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Crystal structure of human dpp-iv in complex with bms-744891
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Structure:
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Dipeptidyl peptidase 4. Chain: a, b. Synonym: adabp, adenosine deaminase complexing protein 2, adcp-2, dipeptidyl peptidase iv, dpp iv, t-cell activation antigen cd26, tp103, dipeptidyl peptidase 4 membrane form, dipeptidyl peptidase iv membrane form, dipeptidyl peptidase 4 soluble form, dipeptidyl peptidase iv soluble form. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: dpp4, adcp2, cd26. Expressed in: komagataella pastoris. Expression_system_taxid: 4922.
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Resolution:
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2.43Å
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R-factor:
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0.226
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R-free:
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0.263
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Authors:
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H.E.Klei
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Key ref:
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P.Devasthale
et al.
(2013).
Optimization of activity, selectivity, and liability profiles in 5-oxopyrrolopyridine DPP4 inhibitors leading to clinical candidate (Sa)-2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778).
J Med Chem,
56,
7343-7357.
PubMed id:
DOI:
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Date:
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08-Jul-13
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Release date:
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04-Sep-13
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PROCHECK
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Headers
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References
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P27487
(DPP4_HUMAN) -
Dipeptidyl peptidase 4 from Homo sapiens
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Seq:
Struc:
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766 a.a.
728 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.4.14.5
- dipeptidyl-peptidase Iv.
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Reaction:
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Release of an N-terminal dipeptide, Xaa-Xbb-|-Xcc, from a polypeptide, preferentially when Xbb is Pro, provided Xcc is neither Pro nor hydroxyproline.
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DOI no:
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J Med Chem
56:7343-7357
(2013)
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PubMed id:
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Optimization of activity, selectivity, and liability profiles in 5-oxopyrrolopyridine DPP4 inhibitors leading to clinical candidate (Sa)-2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778).
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P.Devasthale,
Y.Wang,
W.Wang,
J.Fevig,
J.Feng,
A.Wang,
T.Harrity,
D.Egan,
N.Morgan,
M.Cap,
A.Fura,
H.E.Klei,
K.Kish,
C.Weigelt,
L.Sun,
P.Levesque,
F.Moulin,
Y.X.Li,
R.Zahler,
M.S.Kirby,
L.G.Hamann.
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ABSTRACT
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Optimization of a 5-oxopyrrolopyridine series based upon structure-activity
relationships (SARs) developed from our previous efforts on a number of related
bicyclic series yielded compound 2s (BMS-767778) with an overall activity,
selectivity, efficacy, PK, and developability profile suitable for progression
into the clinic. SAR in the series and characterization of 2s are described.
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