Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38.
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.
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
J David
JD
Becherer
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Eric E
EE
Boros
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Tiffany Y
TY
Carpenter
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
David J
DJ
Cowan
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
David N
DN
Deaton
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Curt D
CD
Haffner
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Michael R
MR
Jeune
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Istvan W
IW
Kaldor
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
J Chuck
JC
Poole
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Frank
F
Preugschat
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Tara R
TR
Rheault
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Christie A
CA
Schulte
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Barry G
BG
Shearer
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Todd W
TW
Shearer
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Lisa M
LM
Shewchuk
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Terrence L
TL
Smalley
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Eugene L
EL
Stewart
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
J Darren
JD
Stuart
GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
John C
JC
Ulrich
D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000378:metabolism; D008567:Membranes, Artificial; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010539:Permeability; D011487:Protein Conformation; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C000603355:2-methyl-4-(((2,3,6-trichlorophenyl)methyl)amino)-8-quinolinecarboxamide; C000603354:4-((2-fluoro-6-(trifluoromethyl)benzyl)amino)-2-methylquinoline-8-carboxamide; D000577:Amides; D000634:Aminoquinolines; D008567:Membranes, Artificial; D011804:Quinolines; D009243:NAD; D051997:ADP-ribosyl Cyclase 1