title: Potent macrocyclic inhibitors of insulin-regulated aminopeptidase (IRAP) by olefin ring-closing metathesis.
abstract: Macrocyclic analogues of angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His(4)-Pro(5)-Phe(6) by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val(1) and Ile(3) 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 Tyr(2) by β(3)hTyr 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.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Andersson
authors.forename: Heidi
authors.initials: H
authors.lastname: Demaegdt
authors.forename: Anders
authors.initials: A
authors.lastname: Johnsson
authors.forename: Georges
authors.initials: G
authors.lastname: Vauquelin
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindeberg
authors.forename: Mathias
authors.initials: M
authors.lastname: Hallberg
authors.forename: Mate
authors.initials: M
authors.lastname: Erdelyi
authors.forename: Anders
authors.initials: A
authors.lastname: Karlen
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D000475:Alkenes / Q000737:chemistry; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C560297:2-(2-((13-amino-2-(4-hydroxybenzyl)-3,14-dioxo-1,4-diazacyclotetradec-7-ene-5-carboxamido)methyl)phenyl)acetic acid; D000475:Alkenes; D007769:Lactams; D018697:Nootropic Agents; D010648:Phenylacetates; D011480:Protease Inhibitors; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase