title: Conformational considerations in the design of dual antagonists of platelet-activating factor (PAF) and histamine.
abstract: Following the discovery of the first dual antagonist of platelet-activating factor (PAF) and histamine, 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)piperidine, Sch 37370, 1, a related series of structures, exemplified by (+/-)-1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b] pyridin-11-yl)piperazine, Sch 40338, 2, were prepared. Interestingly, the compounds exhibited a parallel structure antiallergy activity relationship, suggesting that the two series may adopt a common conformation at the PAF receptor. Conformational analysis led to a proposal for this bioactive conformation accessible to both series. The synthesis of novel conformationally constrained analogues that might mimic the proposed bioactive conformation of these compounds, and the evaluation of their in vitro antiallergy activity form the subject matter of this report.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. james.kaminski@spcorp.com
authors.forename: J J
authors.initials: JJ
authors.lastname: Kaminski
authors.forename: N I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: S C
authors.initials: SC
authors.lastname: Wong
authors.forename: T M
authors.initials: TM
authors.lastname: Chan
authors.forename: M M
authors.initials: MM
authors.lastname: Billah
authors.forename: S
authors.initials: S
authors.lastname: Tozzi
authors.forename: A T
authors.initials: AT
authors.lastname: McPhail
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D017336:Loratadine / Q000737:chemistry / Q000031:analogs & derivatives; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011969:Receptors, Histamine H1 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C121618:7-chloro-3-methyl-1,2,3,4,4aalpha,5,9,10,14balpha,14cbeta-decahydropyrido(3'',2''-6',7')cyclohepta(1',2',3'-4,5)naphtho(2,3-c)pyridine; D018926:Anti-Allergic Agents; D006633:Histamine Antagonists; D007546:Isoquinolines; D010879:Piperazines; D010880:Piperidines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D011969:Receptors, Histamine H1; C121617:Sch 40338; C032727:piperidine; D017336:Loratadine; C063524:N-acetyldesloratadine