title: Rational design, discovery, and synthesis of a novel series of potent growth hormone secretagogues.
abstract: 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.
authors.affiliation: Molecular Research Institute, 2495 Old Middlefield Way, Mountain View, California 94043, USA.
authors.forename: P
authors.initials: P
authors.lastname: Huang
authors.forename: G H
authors.initials: GH
authors.lastname: Loew
authors.forename: H
authors.initials: H
authors.lastname: Funamizu
authors.forename: M
authors.initials: M
authors.lastname: Mimura
authors.forename: N
authors.initials: N
authors.lastname: Ishiyama
authors.forename: M
authors.initials: M
authors.lastname: Hayashida
authors.forename: T
authors.initials: T
authors.lastname: Okuno
authors.forename: O
authors.initials: O
authors.lastname: Shimada
authors.forename: A
authors.initials: A
authors.lastname: Okuyama
authors.forename: S
authors.initials: S
authors.lastname: Ikegami
authors.forename: J
authors.initials: J
authors.lastname: Nakano
authors.forename: K
authors.initials: K
authors.lastname: Inoguchi
mesh_terms: 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
chemical_list: D013841:Thiazepines; D013006:Growth Hormone