Optimization of 1H-tetrazole-1-alkanenitriles as potent orally bioavailable growth hormone secretagogues.
1H-tetrazole-1-alkanenitrile SR-9g exhibits a >10-fold in vivo potency enhancement over the lead nitrile 1 and has acceptable oral bioavailability in rats and dogs. An enantiospecific synthesis of 1H-tetrazole-1-alkanenitrile nitriles 9 has been developed.
Hernández
Andrés S
AS
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. andres.hernandez@bms.com
Swartz
Stephen G
SG
Slusarchyk
Dorothy
D
Yan
Mujing
M
Seethala
R Krishna
RK
Sleph
Paul
P
Grover
Gary
G
Dickinson
Kenneth
K
Giupponi
Leah
L
Harper
Timothy W
TW
Humphreys
W Griffith
WG
Longhi
Daniel A
DA
Flynn
Neil
N
Murphy
Brian J
BJ
Gordon
David A
DA
Biller
Scott A
SA
Robl
Jeffrey A
JA
Tino
Joseph A
JA
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D013006:Growth Hormone / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D010902:Pituitary Gland; D051381:Rats; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
D009570:Nitriles; D013777:Tetrazoles; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System