Stereoselective Preparation of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide, a Potent and Orally Active Dual Neurokinin NK1/NK2 Receptor Antagonist

• Published in: Journal of medicinal chemistry Vol. 46; no. 16; pp. 3508 - 3513
• Main Authors: Gerspacher, Marc, Lewis, Christine, Ball, Howard A, Howes, Colin, Subramanian, Natarajan, Ryffel, Karin, Fozard, John R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 31.07.2003; Amer Chemical Soc
• Subjects: Biological and medical sciences; Chemistry, Medicinal; Life Sciences & Biomedicine; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Respiratory system; Science & Technology; IN-VITRO; FK224; MAMMALIAN TACHYKININ; INFLAMMATION; TACHYKININ RECEPTORS; Nitrogen heterocycle; Lactam; Non peptide compound; Stereoselectivity; Induced bronchoconstriction; Guinea pig; Structure activity relation; Chlorine Organic compounds; Enantiomer; Vinylic compound; Peptidergic receptor; Antagonist; Chemical synthesis; Human; NK1 Tachykinin receptor; Aliphatic compound; Rodentia; Benzene derivatives; Oral administration; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; Affinity; Benzamide derivatives; Carboxamide; NK2 Tachykinin receptor; Pharmacokinetics; Diastereomer; Seven membered ring
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030786m

In a program aimed at the development of neurokinin antagonists, N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1, DNK333) has been discovered as a potent and balanced neurokinin (tachykinin) NK1/NK2 receptor antagonist. Enantiomerically pure (>99.5% ee) 1 can be prepared in 6 + 1 synthetic steps starting from commercially available optically active BOC-d-3,4-dichlorophenylalanine in an overall yield of ca. 25−30%. 1 showed potent affinities to cloned human NK1 (pK i = 8.38) and NK2 (pK i = 8.02) receptors. When 1 was compared to the other possible three diastereoisomers, it could be demonstrated that only the R,R-isomer (1) exhibits potent and balanced affinity for the cloned human NK1 and NK2 receptors. 1 exhibited favorable pharmacokinetic properties in guinea pigs following oral administration and demonstrated in vivo activity in pharmacological models of substance P- and neurokinin A (NKA)-induced bronchoconstriction in guinea pigs after intravenous and in squirrel monkeys after oral application.