Development of analytical and preparative chromatographic separations of novel growth hormone secretagogue compounds

• Published in: Journal of Chromatography A Vol. 872; no. 1; pp. 75 - 84
• Main Authors: Kennedy, Joseph H, Bowers, John L, Dodge, Jeffrey A, Lugar, Charles W, Shepherd, Timothy A, Sharp, V.Scott
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 03-03-2000; Elsevier
• Subjects: Analysis; Biological and medical sciences; General pharmacology; Growth Hormone - metabolism; Growth hormone secretagogue; Heterocyclic Compounds - analysis; Heterocyclic Compounds - isolation & purification; Medical sciences; Pharmacology. Drug treatments; Stereoisomerism; Structure-Activity Relationship; Growth hormone secretagogue; Preparative chromatography; Reaction intermediate; Chemical analysis; Ultraviolet detector; Purification; Separation; Peptidomimetic compound; Enantiomer; Somatotropin hormone; HPLC chromatography; Non peptide compound; Diastereomer
• ISSN: 0021-9673
• DOI: 10.1016/S0021-9673(99)01286-8

Chromatographic separations of new growth hormone secretagogue compounds were developed to support structure–activity relationship (SAR) studies in conjunction with lead optimization. These new compounds differed from Merck’s MK-677 by having two chiral centers and thus diastereomeric mixtures were generated. Separation of initial compounds in the SAR was achieved on a Kromasil C
18 column using an ammonium acetate buffer and acetonitrile. However, additional candidates were not separable on C
18 columns and a chiral Kromasil CHI-DMB column was used to resolve the diastereomeric compounds. The Kromasil CHI-DMB packing was also used in a preparative chromatographic system to resolve multigram quantities of secretagogue candidates for testing. Chiral separations of different intermediates were also developed in support of evolution of an asymmetric synthetic route. This report summarizes development of the preparative chromatographic system used to purify diastereomeric mixtures and chiral separations of intermediates in the synthesis.