Discovery of BI 1356: A highly potent and long-acting DPP-IV inhibitor with a xanthine scaffold

MEDI 24

Frank Himmelsbach, frank.himmelsbach@bc.boehringer-ingelheim.com1, Klaus Dugi2, Matthias Eckhardt1, Holger Fuchs3, Ulrike Graefe-Mody3, Brian Guth4, Elke Langkopf1, Ralf Lotz4, Michael Mark5, Herbert Nar6, Peter Sieger4, Moh Tadayyon5, and Leo Thomas5. (1) Department of Chemical Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany, (2) Department of Therapeutic Area Metabolism, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany, (3) Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany, (4) Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany, (5) Department of Metabolic Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany, (6) Department of Lead Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany
Dipeptidyl peptidase IV (DPP-IV) is a serine protease which specifically cleaves dipeptides after a penultimate N-terminal proline or alanine. DPP-IV is involved in the degradation of a number of peptides, most notably of the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). GLP-1 exerts a potent glucose-dependent insulinotropic action and thereby contributes to the maintenance of glycaemic control. In addition, it inhibits glucagon release from pancreatic alpha-cells and in animal models has been shown to preserve beta-cell mass. Therefore, DPP-IV inhibitors are a promising new class of antidiabetic agents with a low risk of hypoglycaemia and a potential for disease modification. Here, we describe the discovery process that started with a micromolar screening hit and, after optimization of the key substituents at N1, N-7 and C-8 of the xanthine, culminated in the identification of BI 1356 (IC50 = 1 nM) that is currently in Phase IIb clinical trials. The SAR, in vivo characterization and the X-ray structure of BI 1356 in complex with DPP-IV will be discussed.
 

General Oral Session
1:30 PM-4:50 PM, Sunday, August 19, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007