Potent macrocyclic inhibitors of insulin-regulated aminopeptidase (IRAP) by olefin ring-closing metathesis

Article abstract of DOI:10.1021/jm200036n

Macrocyclic analogues of angiotensin IV (Ang IV, Val¹-Tyr ²-Ile³-His⁴-Pro⁵-Phe⁶) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His⁴-Pro ⁵-Phe⁶ by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val¹ and Ile³ by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon-carbon bridge was assessed. The ring size generally affects the potency more than the carbon-carbon bond characteristics. Replacing Tyr² by β³hTyr or Phe is accepted, while N-methylation of Tyr ² is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (K_i = 4.1 nM) and 19 (K_i = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.