title: Ortho-substituted benzofused macrocyclic lactams as zinc metalloprotease inhibitors.
abstract: The design and preparation of ortho-substituted benzofused macrocyclic lactams are described. The benzofused macrocyclic lactams were designed as neutral endopeptidase 24.11 (NEP) inhibitors. Docking studies were carried out in a model of thermolysin (TLN) using the MACROMODEL and QXP modeling programs to select suitable ring sizes. These studies predicted that the 11-, 12-, and 13-membered ring macrocyclic lactams would be active in both enzymes TLN and NEP. Good predictability of experimental results, within this series, of binding to thermolysin and to a lesser extent to NEP was observed. A visual comparison, docked at the active site of TLN, is presented for thiorphan, a 10-membered ring macrocycle and an 11-membered ring benzofused macrocyclic lactam. Potent inhibition of both NEP and thermolysin was obtained. The 11-membered ring macrocycle 25a is the most potent inhibitor from this series of compounds (TLN IC50 = 68 nM; NEP IC50 = 0.9 nM). The effects of prodrug 44b administered at 10 mg/kg po on plasma atrial natriuretic peptide (ANP) levels in conscious rats was greater than 200% over a 4 h period.
authors.affiliation: Research Department, Novartis Pharmaceuticals Corporation, Summit, New Jersey 07901, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Ksander
authors.forename: R
authors.initials: R
authors.lastname: de Jesus
authors.forename: A
authors.initials: A
authors.lastname: Yuan
authors.forename: R D
authors.initials: RD
authors.lastname: Ghai
authors.forename: A
authors.initials: A
authors.lastname: Trapani
authors.forename: C
authors.initials: C
authors.lastname: McMartin
authors.forename: R
authors.initials: R
authors.lastname: Bohacek
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001665:Binding Sites; D004357:Drug Synergism; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D012984:Software; D015244:Thiorphan / Q000737:chemistry
chemical_list: D007769:Lactams; D009320:Atrial Natriuretic Factor; D015244:Thiorphan; D015260:Neprilysin