DESIGN AND SYNTHESIS OF POTENT MACROCYCLIC BENZOLACTAM GROWTH-HORMONESECRETAGOGUES

The synthesis of a variety of potent macrocyclic growth hormone secret agogues, i.e. 5, 9, 12, and 20-22, based on the known lead structure L -692,429 (1) is described. These conformationally constrained growth h ormone secretagogues were prepared by joining the two essential pharma cophores, 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 a nalog was found to be L-744,080 (21), a derivative in which a 2'-carbo xamide moiety al 1,1'-biphenyl is N,O-joined to the OH group of the (2 -hydroxypropyl)amino-acid side chain by a C-4 ester linker. This poten t analog may be useful in determining the bound conformation of the be nzolactam class of growth hormone secretagogues at the newly identifie d GHS receptor. L-744,080 (21) with an ED50 of 20 nM was up to fifty t imes more potent than the seco-acid precursor and 3-fold more potent t han the parent 2'-tetrazole compound L-692,429 (1).