title: Design, synthesis and evaluation of MCH receptor 1 antagonists--Part III: Discovery of pre-clinical development candidate BI 186908.
abstract: Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11 g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic administration of BI 186908 resulted in significant body weight reduction comparable to sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile, BI 186908 was advanced to pre-clinical development.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany. Electronic address: thorsten.oost@boehringer-ingelheim.com.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Oost
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Heckel
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Kley
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehmann
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Müller
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Roth
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rudolf
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Arndt
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Budzinski
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Lenter
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Ralf R H
authors.initials: RR
authors.lastname: Lotz
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Gerd-Michael
authors.initials: GM
authors.lastname: Maier
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Markert
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Leo
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Stenkamp
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001067:Appetite Depressants / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D003503:Cyclobutanes / Q000494:pharmacology; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D008064:Lipidoses / Q000188:drug therapy; D008862:Microsomes, Liver / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D001067:Appetite Depressants; C000606496:BI 186908; D003503:Cyclobutanes; D051638:Ether-A-Go-Go Potassium Channels; C491208:MCHR1 protein, rat; D010743:Phospholipids; D026902:Potassium Channel Blockers; D011719:Pyrazines; D011724:Pyridazines; D011725:Pyridines; D017481:Receptors, Somatostatin; C058254:sibutramine
keywords: MCH-R1 antagonists; Melanin-concentrating hormone (MCH); Phospholipidosis; Pyridazinone chemistry; hERG inhibition