title: Structure-based drug design and the discovery of aliskiren (Tekturna): perseverance and creativity to overcome a R&D pipeline challenge.
abstract: At Ciba-Geigy (now Novartis), the clinical development of the CGP38560 renin inhibitor was halted due to insufficient pharmacokinetics. This indicated that the peptidomimetic approach to the development of antihypertensive agents was improper. Real non-peptide drug candidates were then expected to provide the necessary framework for obtaining the desired properties. For this purpose a homology model of the enzyme was used to characterize the binding mode of CGP38560 in complex with the renin model and served as a basis for the four chemistry laboratories that were assigned to this project. The renin team worked in a full structure-based perspective with this model, and four chemically-unrelated non-peptide series were discovered acting as renin inhibitors at the 1-3 nanomolar level. One of these leads was selected for further development and led to Aliskiren, which has been just approved by the FDA. Here is presented the successful structure-based strategy that enabled the discovery of several non-peptide inhibitors and the recent launch of a new drug that will be commercialized in the United States under the name Tekturna (for the treatment of high blood pressure as monotherapy or in combination with other high blood pressure medications).
authors.affiliation: Synergix Ltd, Technology Park, Building #1, Jerusalem 91487, Israel. claude@drug.design.com
authors.forename: Nissim Claude
authors.initials: NC
authors.lastname: Cohen
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017277:Drug Approval; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005650:Fumarates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014481:United States; D014486:United States Food and Drug Administration; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D005650:Fumarates; D000092502:Renin Inhibitors; C446481:aliskiren