MEDI 424 |
| Molecules that interact with the human motilin receptor (hMOT-r) have potential for the treatment of GI disorders associated with altered gut motility. As part of our ongoing effort towards the discovery of new small molecule antagonists to hMOT-r, we have synthesized a collection of macrocyclic peptidomimetics of general structure (A). Incorporation of unnatural amino acids (1) and (2) led to potent antagonists. Then, guanidine isosteric modifications were incorporated into the macrocyclic structure, under the form of heterocyclic residues (3) and (4). Variations around substituent X in combination with the latter modifications ultimately led to low nanomolar antagonists to hMOT-r (functional IC50 1-10 nM). The synthesis of macrocycles as well as elaboration of these unprecedented unnatural amino acids will be described. The SAR around this particular class of molecules will be detailed as well.
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General Poster Session
7:00 PM-9:00 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster
Division of Medicinal Chemistry |
