Design and synthesis of tetrazole-based growth hormone secretagogue: the SAR studies of the O-benzyl serine side chain.
The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 (2). The ortho position of the benzyl moiety was found to be favorable for introduction of substituents. A series of ortho-substituted compounds were synthesized with improved in-vitro and in-vivo activity. Among them, the biphenyl compound 2p shows twofold improvement in potency compared to its parent compound BMS-317180 (2).
Li
Jun
J
Discovery Chemistry, Bristol Myers Squibb, Princeton, NJ 08543, USA. jun.li@bms.com
Chen
Stephanie Y
SY
Tao
Shiwei
S
Wang
Haixia
H
Li
James J
JJ
Swartz
Steve
S
Musial
Christa
C
Hernandez
Andres A
AA
Flynn
Neil
N
Murphy
Brian J
BJ
Beehler
Blake
B
Dickinson
Kenneth E
KE
Giupponi
Leah
L
Grover
Gary
G
Seethala
Ramakrishna
R
Sleph
Paul
P
Slusarchyk
Dorothy
D
Yan
Mujing
M
Humphreys
William G
WG
Zhang
Hongjian
H
Ewing
William R
WR
Robl
Jeffrey A
JA
Gordon
David
D
Tino
Joseph A
JA
D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D015195:Drug Design; D013006:Growth Hormone / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D012694:Serine / Q000031:analogs & derivatives* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
C526808:4-(hydroxybutyl)carbamic acid 2-(5-(1-(2-amino-2-methylpropionylamino)-2-benzyloxyethyl)tetrazol-1-yl)ethyl ester; D002219:Carbamates; D013777:Tetrazoles; D012694:Serine; C052987:O-benzoylserine; D013006:Growth Hormone