2. Academic Validation
  3. Design, synthesis and evaluation of MCH receptor 1 antagonists--Part III: Discovery of pre-clinical development candidate BI 186908

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part III: Discovery of pre-clinical development candidate BI 186908

  • Bioorg Med Chem Lett. 2015 Aug 15;25(16):3275-80. doi: 10.1016/j.bmcl.2015.05.065.
Thorsten Oost 1,  Armin Heckel 2,  Jörg T Kley 2,  Thorsten Lehmann 2,  Stephan Müller 2,  Gerald J Roth 2,  Klaus Rudolf 2,  Kirsten Arndt 3,  Ralph Budzinski 3,  Martin Lenter 3,  Ralf R H Lotz 4,  Gerd-Michael Maier 4,  Michael Markert 4,  Leo Thomas 3,  Dirk Stenkamp 2
Affiliations

Affiliations

  • 1 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.
  • 2 Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
  • 3 Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
  • 4 Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support, Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
PMID: 26105194 DOI: 10.1016/j.bmcl.2015.05.065
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.

Keywords

MCH-R1 antagonists; Melanin-concentrating hormone (MCH); Phospholipidosis; Pyridazinone chemistry; hERG inhibition.

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