New proline mimetics: synthesis of thrombin inhibitors incorporating cyclopentane- and cyclopentenedicarboxylic acid templates in the P2 position. Binding conformation investigated by X-ray crystallography.
With the aim to prepare nonpeptidic thrombin inhibitors, the amino acids of the thrombin-inhibiting tripeptide chain D-Phe-Pro-Arg were replaced with isosteres. Arg was replaced with the more rigid P1 truncated p-amidinobenzylamine (Pab), Pro with either cyclopentane-1, 2-dicarboxylic acid or cyclopentene-1,5-dicarboxylic acid, and D-Phe with a series of readily available lipophilic amines. One of the most potent compounds (25, pIC(50) = 6.01) in these series was cocrystallized with thrombin where the X-ray crystal structure provide insight to the structure-activity relationship (SAR).
Nöteberg
D
D
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
Brånalt
J
J
Kvarnström
I
I
Linschoten
M
M
Musil
D
D
Nyström
J E
JE
Zuccarello
G
G
Samuelsson
B
B
D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011392:Proline / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013698:Templates, Genetic; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000925:Anticoagulants; D003517:Cyclopentanes; D007202:Indicators and Reagents; C409963:cyclopentenedicarboxylic acid; D011392:Proline; D013917:Thrombin