2. Academic Validation
  3. Discovery of novel, orally active dual NK1/NK2 antagonists

Discovery of novel, orally active dual NK1/NK2 antagonists

  • Bioorg Med Chem Lett. 2001 Oct 22;11(20):2769-73. doi: 10.1016/s0960-894x(01)00572-8.
P R Bernstein 1,  D Aharony,  J S Albert,  D Andisik,  H G Barthlow,  R Bialecki,  T Davenport,  R F Dedinas,  B T Dembofsky,  G Koether,  B J Kosmider,  K Kirkland,  C J Ohnmacht,  W Potts,  W L Rumsey,  L Shen,  A Shenvi,  S Sherwood,  D Stollman,  K Russell
Affiliations

Affiliation

  • 1 CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA. peter.bernstein@astrazeneca.com
PMID: 11591520 DOI: 10.1016/s0960-894x(01)00572-8
Abstract

Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, respectively). In functional assays ZD6021 had, at 10(-7)M, in human pulmonary artery pK(B)=8.9 and in human bronchus pK(B)=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED(50)=0.5mg/kg, and NK2 mediated bronchoconstriction, ED(50)=13mg/kg.

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