Discovery of novel, orally active dual NK1/NK2 antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 11; no. 20; pp. 2769 - 2773
• Main Authors: BERNSTEIN, Peter R, AHARONY, David, KOSMIDER, Benedict J, KIRKLAND, Karin, OHNMACHT, Cyrus J, POTTS, William, RUMSEY, William L, LIHONG SHEN, SHENVI, Ashok, SHERWOOD, Scott, STOLLMAN, David, RUSSELL, Keith, ALBERT, Jeffrey S, ANDISIK, Donald, BARTHLOW, Herbert G, BIALECKI, Russell, DAVENPORT, Timothy, DEDINAS, Robert F, DEMBOFSKY, Bruce T, KOETHER, Gerard
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 22-10-2001
• Subjects: Administration, Oral; Animals; Benzamides - chemistry; Benzamides - pharmacokinetics; Benzamides - pharmacology; Biological and medical sciences; Dogs; Dose-Response Relationship, Drug; Guinea Pigs; Medical sciences; Models, Animal; Neurokinin-1 Receptor Antagonists; Pharmacology. Drug treatments; Piperidines - chemistry; Piperidines - pharmacokinetics; Piperidines - pharmacology; Rats; Receptors, Neurokinin-2 - antagonists & inhibitors; Respiratory system; Structure-Activity Relationship; Sulfoxides - chemistry; Sulfoxides - pharmacokinetics; Sulfoxides - pharmacology; Nitrile; Rat; Selectivity; Dose activity relation; Bronchoconstriction; Guinea pig; Structure activity relation; Chlorine Organic compounds; Piperidine derivatives; Bicyclic compound; Antagonist; Tachykinin receptor; Chemical synthesis; Dog; Fissipedia; Carnivora; Respiratory disease; Rodentia; Oral administration; Condensed benzenic compound; In vitro; Naphthalene derivatives; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Sulfoxide; Carboxamide; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/s0960-894x(01)00572-8

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.