title: Design, synthesis and evaluation of MCH receptor 1 antagonists--Part II: Optimization of pyridazines toward reduced phospholipidosis and hERG inhibition.
abstract: Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated. During optimization several issues of the initial lead structures had to be resolved, such as selectivity over related GPCRs, inhibition of the hERG channel as well as the potential to induce phospholipidosis. Utilizing property-based design, we could demonstrate that all parameters can significantly be improved by consequently increasing the polarity of the compounds. By this strategy, we succeeded in identifying potent and orally available MCH-R1 antagonists with good selectivity over M1 and 5-HT2A and an improved safety profile with respect to hERG inhibition and phospholipidosis.
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: geraldroth@boehringer-ingelheim.com.
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: 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 G
authors.initials: SG
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: 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: 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 Cardiometabolic Research, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schindler
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; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D008064:Lipidoses / Q000188:drug therapy*; D010743:Phospholipids / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D051638:Ether-A-Go-Go Potassium Channels; C491208:MCHR1 protein, rat; D010743:Phospholipids; D026902:Potassium Channel Blockers; D011724:Pyridazines; D044402:Receptor, Serotonin, 5-HT2A; D017481:Receptors, Somatostatin; D012702:Serotonin Antagonists
keywords: MCH-R1 antagonists; Melanin-concentrating hormone (MCH); Phospholipidosis; Pyridazine chemistry; hERG inhibition