Design and synthesis of substituted N-methylbenzamide analogues derived from SR 48,968 as neurokinin-2 receptor antagonists.
A series of N-methylbenzamide analogues (2-18) that is structurally derived from SR 48,968, a potent neurokinin-2 (NK(2)) receptor antagonist (pK(b)9.1), has been obtained using asymmetric synthesis. Isothiocyanato-N-methylbenzamide (10-12) and bromoacetamido-N-methylbenzamide derivatives (16-18) have been designed to serve as potential electrophilic affinity labels. Nitro-N-methylbenzamide (4-6) and acetamido-N-methylbenzamide (13-15) were designed to serve as the nonelectrophilic controls for these ligands. Functional assay results using guinea pig trachea indicate that electrophilic N-methylbenzamide analogues exhibit potent but surmountable NK(2) receptor antagonist activity. Several members of this series (2, 3, 7-9) exhibit potent NK(2) receptor antagonist potencies with pK(b) values in the range of 9.1-9.7. para-Fluoro substituted analogue 3 was found to be highly potent with a pK(b) of 9.7.
Huang
Shih-Chung
SC
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439, USA.
Undem
Bradley
B
Korlipara
Vijaya
V
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D001549:Benzamides; D008024:Ligands; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C073839:SR 48968; C038530:N-methylbenzamide