Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions |
umls-concept:C0183683,
umls-concept:C0205177,
umls-concept:C0205208,
umls-concept:C0205314,
umls-concept:C0205531,
umls-concept:C0220781,
umls-concept:C0226896,
umls-concept:C0243071,
umls-concept:C0344211,
umls-concept:C0439064,
umls-concept:C0439831,
umls-concept:C0442027,
umls-concept:C0671106,
umls-concept:C0679622,
umls-concept:C1171411,
umls-concept:C1317973,
umls-concept:C1521721,
umls-concept:C1527148,
umls-concept:C1527415,
umls-concept:C1707689,
umls-concept:C1880355,
umls-concept:C1883254,
umls-concept:C2746042
|
| pubmed:issue |
3
|
| pubmed:dateCreated |
1998-2-27
|
| pubmed:abstractText |
Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties via a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P2-P1 template 7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)-prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, Ki = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 micrograms/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to further evaluation as a possible treatment for thrombogenic disorders.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jan
|
| pubmed:issn |
0022-2623
|
| pubmed:author |
pubmed-author:ApplebyS DSD,
pubmed-author:BradyS FSF,
pubmed-author:ChenI WIW,
pubmed-author:CoonJ MJM,
pubmed-author:GardellS JSJ,
pubmed-author:HolahanM AMA,
pubmed-author:LewisS DSD,
pubmed-author:LinJ HJH,
pubmed-author:LucasB JBJ,
pubmed-author:LummaW CWC,
pubmed-author:LyleE AEA,
pubmed-author:LyonsK RKR,
pubmed-author:Naylor-OlsenA MAM,
pubmed-author:RamageP IPI,
pubmed-author:SmithG MGM,
pubmed-author:StaufferK JKJ,
pubmed-author:StranieriM TMT,
pubmed-author:VaccaJ PJP,
pubmed-author:VastagKK
|
| pubmed:issnType |
Print
|
| pubmed:day |
29
|
| pubmed:volume |
41
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
401-6
|
| pubmed:dateRevised |
2003-11-14
|
| pubmed:meshHeading |
pubmed-meshheading:9464370-Animals,
pubmed-meshheading:9464370-Antithrombins,
pubmed-meshheading:9464370-Biological Availability,
pubmed-meshheading:9464370-Dogs,
pubmed-meshheading:9464370-Drug Design,
pubmed-meshheading:9464370-Haplorhini,
pubmed-meshheading:9464370-Models, Molecular,
pubmed-meshheading:9464370-Pyrrolidines,
pubmed-meshheading:9464370-Rats,
pubmed-meshheading:9464370-Structure-Activity Relationship
|
| pubmed:year |
1998
|
| pubmed:articleTitle |
Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460): coapplication of structure-based design and rapid multiple analogue synthesis on solid support.
|
| pubmed:affiliation |
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
|
| pubmed:publicationType |
Journal Article
|