title: Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414.
abstract: Despite recent approvals of anti-obesity drugs there is still a high therapeutic need for alternative options with higher efficacy in humans. As part of our MCH-R1 antagonist program for the treatment of obesity, a series of biphenylacetamide HTS hits was evaluated. Several issues of the initial lead structures had to be resolved, such as potency, selectivity over related GPCRs and P-gp efflux limiting brain exposure in this series. We could demonstrate that all parameters can be significantly improved by structural modifications resulting in BI 414 as a potent and orally available MCH-R1 antagonist tool compound with acceptable in vivo efficacy in an animal model of obesity.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany. Electronic address: stephan_georg.mueller@boehringer-ingelheim.com.
authors.forename: Stephan G
authors.initials: SG
authors.lastname: Müller
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, 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, 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, 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, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Lustenberger
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, 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, 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, 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, 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, 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, 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 Medicinal Chemistry, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Stenkamp
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000480:Alkynes / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004435:Eating / Q000187:drug effects; D057166:High-Throughput Screening Assays; D009765:Obesity / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000480:Alkynes; D019440:Anti-Obesity Agents; C000606495:BI 414; D065607:Cytochrome P-450 Enzyme Inhibitors; C491208:MCHR1 protein, rat; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D017481:Receptors, Somatostatin; D019389:Cytochrome P-450 CYP2D6
keywords: Alkynes; MCH-R1 antagonists; Melanin-concentrating hormone (MCH)