2. Academic Validation
  3. N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II

N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II

  • Bioorg Med Chem Lett. 2006 Nov 15;16(22):5752-6. doi: 10.1016/j.bmcl.2006.08.085.
Jason M Elliott 1,  Robert W Carling,  Gary G Chicchi,  James Crawforth,  Peter H Hutson,  A Brian Jones,  Sarah Kelly,  Rose Marwood,  Georgina Meneses-Lorente,  Elena Mezzogori,  Fraser Murray,  Michael Rigby,  Inmaculada Royo,  Michael G N Russell,  Duncan Shaw,  Bindi Sohal,  Kwei Lan Tsao,  Brian Williams
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. [email protected]
PMID: 16950617 DOI: 10.1016/j.bmcl.2006.08.085
Abstract

Introduction of selected amine containing side chains into the 3-position of N',2-diphenylquinoline-4-carbohydrazide based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI(Kr) affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ(90) 7 mg/kg po; plasma Occ(90) 0.4 microM) and has good selectivity and excellent PK properties.

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