95. Design and Synthesis of Potent Macrocyclic Benzolactam Growth Hormone Secretagogues

Robert J. DeVita, Alison J. Frontier, William R. Schoen, Matthew J. Wyvratt, Michael H. Fisher, Kang Cheng, Wanda W.S. Chan, Bridget S. Butler, Roy G. Smith

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The synthesis of a variety of potent macrocyclic growth hormone secretagogues, i.e. 5, 9, 12, and 20-22, based on the known lead structure L-692,429 (1) is described. These conformationally constrained growth hormone secretagogues were prepared by joining the two essential pharmacophores, the amino-acid side chain at the 1H-1-benzazepine moiety and the 1,1′-biphenyl moiety with a variety of linkers. The most potent analog was found to be L-744,080 (21), a derivative in which a 2′-carboxamide moiety at 1,1′-biphenyl is N,O-joined to the OH group of the (2-hydroxypropyl)amino-acid side chain by a C4 ester linker. This potent analog may be useful in determining the bound conformation of the benzolactam class of growth hormone secretagogues at the newly identified GHS receptor. L-744,080 (21) with an ED50 of 20 nM was up to fifty times more potent than the seco-acid precursor and 3-fold more potent than the parent 2′-tetrazole compound L-692,429 (1).

Original languageEnglish
Pages (from-to)1244-1259
Number of pages16
JournalHelvetica Chimica Acta
Volume80
Issue number4
DOIs
StatePublished - 1997
Externally publishedYes

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