title: Discovery of carmegliptin: a potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
abstract: Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.
authors.affiliation: F Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland. patrizio.mattei@roche.com
authors.forename: Patrizio
authors.initials: P
authors.lastname: Mattei
authors.forename: Markus
authors.initials: M
authors.lastname: Boehringer
authors.forename: Patrick
authors.initials: P
authors.lastname: Di Giorgio
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
authors.forename: Joerg
authors.initials: J
authors.lastname: Huwyler
authors.forename: Buelent
authors.initials: B
authors.lastname: Koçer
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.forename: Bernd M
authors.initials: BM
authors.lastname: Loeffler
authors.forename: Alexander
authors.initials: A
authors.lastname: Macdonald
authors.forename: Robert
authors.initials: R
authors.lastname: Narquizian
authors.forename: Etienne
authors.initials: E
authors.lastname: Rauber
authors.forename: Elena
authors.initials: E
authors.lastname: Sebokova
authors.forename: Urs
authors.initials: U
authors.lastname: Sprecher
mesh_terms: D000818:Animals; D017322:Clinical Trials, Phase II as Topic; D018360:Crystallography, X-Ray; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D004285:Dogs; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D008252:Macaca fascicularis; D051379:Mice; D011807:Quinolizines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker
chemical_list: D003692:Delayed-Action Preparations; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011807:Quinolizines; C552198:carmegliptin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4