Rational design, discovery, and synthesis of a novel series of potent growth hormone secretagogues.
In the joint experimental and computational efforts reported here to obtain novel chemical entities as growth hormone secretagogues (GHSs), a small database of peptides and non-peptides known to have GHS activity was used to generate and assess a 3D pharmacophore for this activity. This pharmacophore was obtained using a systematic and efficient procedure, "DistComp", developed in our laboratory. The 3D pharmacophore identified was then used to search 3D databases to explore chemical structures that could be novel GHSs. A number of these were chosen for synthesis and assessment of their ability to release growth hormone (GH) from rat pituitary cells. Among the compounds tested, those with a benzothiazepin scaffold were discovered with micromolar activity. To facilitate lead optimization, a second program, a site-dependent fragment QSAR procedure was developed. This program calculates a library of chemical and physical properties of "fragments" or chemical components in a known pharmacophore and determines which, if any, of these properties are important for the observed activity. The combined use of the 3D pharmacophore and the results of the site-dependent fragment QSAR analysis led to the discovery and synthesis of a novel series of potent GHSs, a number of which had nanomolar in vitro activity.
Huang
P
P
Molecular Research Institute, 2495 Old Middlefield Way, Mountain View, California 94043, USA.
Loew
G H
GH
Funamizu
H
H
Mimura
M
M
Ishiyama
N
N
Hayashida
M
M
Okuno
T
T
Shimada
O
O
Okuyama
A
A
Ikegami
S
S
Nakano
J
J
Inoguchi
K
K
D000818:Animals; D016208:Databases, Factual; D015195:Drug Design; D013006:Growth Hormone / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D008958:Models, Molecular; D018716:Molecular Mimicry; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D013841:Thiazepines; D013006:Growth Hormone