 |
PDBsum entry 4xjs
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase, transferase
|
PDB id
|
|
|
|
4xjs
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Discovery of 4-Amino-8-Quinoline carboxamides as novel, Submicromolar inhibitors of NAD-Hydrolyzing enzyme cd38.
|
|
|
Authors
|
|
J.D.Becherer,
E.E.Boros,
T.Y.Carpenter,
D.J.Cowan,
D.N.Deaton,
C.D.Haffner,
M.R.Jeune,
I.W.Kaldor,
J.C.Poole,
F.Preugschat,
T.R.Rheault,
C.A.Schulte,
B.G.Shearer,
T.W.Shearer,
L.M.Shewchuk,
T.L.Smalley,
E.L.Stewart,
J.D.Stuart,
J.C.Ulrich.
|
|
|
Ref.
|
|
J Med Chem, 2015,
58,
7021-7056.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Starting from the micromolar 8-quinoline carboxamide high-throughput screening
hit 1a, a systematic exploration of the structure-activity relationships (SAR)
of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the
identification of approximately 10-100-fold more potent human CD38 inhibitors.
Several of these molecules also exhibited pharmacokinetic parameters suitable
for in vivo animal studies, including low clearances and decent oral
bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to
elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO)
C57BL/6 mouse model. These inhibitor tool compounds will enable further
biological studies of the CD38 enzyme as well as the investigation of the
therapeutic implications of NAD enhancement in disease models of abnormally low
NAD.
|
|
|
|
|
|
|
