Identification of a new series of non-peptidic NK 3 receptor antagonists Karsten Juhl a,⇑ , Tore Hansen a,  , Jan Kehler a , Nikolay A. Khanzhin a , Morten B. Nørgaard a , Thomas Ruhland a , Dorrit B. Larsen a , Klaus G. Jensen a , Björn Steiniger-Brach b , Søren M. Nielsen b , Klaus B. Simonsen a a Discovery Chemistry and DMPK, H. Lundbeck A/S, Otilliavej 9, DK 2500 Valby, Denmark b Discovery Pharmacology Research, H. Lundbeck, Otilliavej 9, DK 2500 Valby, Denmark article info Article history: Received 2 November 2010 Revised 29 December 2010 Accepted 31 December 2010 Available online 13 January 2011 Keywords: NK 3 antagonist Schizophrenia Cyclopropane Senktide induced hypoactivity abstract The identification and structure–activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxam- ides as novel NK 3 receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK 3 receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils. Ó 2011 Elsevier Ltd. All rights reserved. The NK 3 receptor is one of three known neurokinin receptors. The NK 3 receptor is expressed both centrally and in some peripheral or- gans. 1–3 The expression in the central nervous system (CNS) and the modulatory effect on various monoaminergic transmitter systems 4 make NK 3 receptor antagonists interesting as potential therapeutic agents for the treatment of CNS diseases such as schizophrenia, 5 Par- kinsons disease, 6 panic attacks and major depressive disorder. 7 N NH O OH N N O Cl Cl N O N NH O N H S O O Talnetant Osanetant AZD2624 Three non-peptide based NK 3 receptor antagonists have entered the clinical trials: Talnetant and AZD2624 from a common 2-aryl- 4-carboxamide-quinoline core structure and Osanetant from a piperidine amide series. All three compounds have been with- drawn from further clinical development. As a result of an NK 3 -focused screening campaign including compounds from a previous neurokinin project, we identified a new structural class of non-peptidic NK 3 receptor antagonists. Specifically, we found lead compound 1a and structurally related analogues that derived from a tri-substituted cyclopropane scaffold. This scaffold is capable of arranging three distinct func- tionalities (a carboxamide, an aryl and an aminomethyl) in a well-defined orientation. Compound 1a displays high affinity for the NK 3 receptor (K i = 5.9 nM) and selectivity towards the NK 1 and NK 2 receptors (K i = 130 nM and K i = 88 nM, respectively). 8 The synthesis of 1a (and derivatives) commenced from a diazo- transfer from p-acetamidobenzenesulfonyl azide (p-ABSA) to the phenyl acetic acid allyl ester 2 (see Fig. 1). The resulting diazo com- pound 3 was converted through intramolecular cyclopropanation to the racemic lactone 4. The racemate was resolved either through chiral chromatography separation of the two enantiomers (1S,5R)- 4 and (1R,5S)-4 or through a series of chemical modifications involv- ing (a) lewis acid mediated lactone opening with (R)-a-methyl benzyl amine, (b) separation of the resulting two diastereomers 5a and 5b, (c) acid-mediated conversion of 5a and 5b to the enantio- meric pure lactones. Alternatively, analogues of (1S,5R)-4 were synthesized from (R)-(À)-epichlorohydrin and the appropriate benzyl cyanide. 9 The synthesis continued by opening the lactone ring with various benzyl amines mediated by AlCl 3 . Conversion of the alcohol 6 to the bromide and subsequent treatment with an amine completed the synthesis of 1a. 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.12.135 ⇑ Corresponding author. Tel.: +45 36434041; fax: +45 36438237. E-mail address: kaju@lundbeck.com (K. Juhl).   Present address: University of Oslo, Department of Chemistry, Sem Sælands vei 26, 0315 Oslo, Norway. Bioorganic & Medicinal Chemistry Letters 21 (2011) 1498–1501 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl