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

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).