Nascent structure-activity relationship study of a diastereomeric series of kappa opioid receptor antagonists derived from CJ-15,208

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 13, 2009, Pages 3647-3650

  Dolle, Roland E ^a   Michaut, Mathieu ^a   Martinez Teipel, Blanca ^a   Seida, Pamela R ^a   Ajello, Christopher W ^a   Muller, Alison L ^a   DeHaven, Robert N ^a   Carroll, Patrick J ^b  

^a ADOLOR CORPORATION   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

CJ 15,208; Cyclic tetrapeptide; Kappa opioid receptor antagonist; Mu opioid receptor antagonist; Opiate; SAR; Structure activity relationship

Indexed keywords

ACETYLPHENYLALANYLTRYPTOPHYLPHENYLALANYLPROLINAMIDE; ACETYLPROLYLPHENYLALANYLTRYPTOPHANAMIDE; CJ 15208; CYCLO(ALANYLPROLYLPHENYLALANYLTRYPTOPHAN); CYCLO(PHENYLALANYLPROLYLPHENYLALANYLTRYPTOPHAN); KAPPA OPIATE RECEPTOR ANTAGONIST; MU OPIATE RECEPTOR; TETRAPEPTIDE; TRYPTOPHAN; UNCLASSIFIED DRUG;

ARTICLE; DIASTEREOISOMER; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; HUMAN; IC 50; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; HUMANS; PEPTIDES, CYCLIC; RECEPTORS, OPIOID, KAPPA; RECEPTORS, OPIOID, MU; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 66349112225     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.04.105     Document Type: Article

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25. Conformations of 12 and 13 were generated using the stochastic conformation search protocol and MMFF94x forcefield in MOE 2008.10 (Chemical Computing Group, Montreal, Quebec, Canada, www.chemcomp.com). Forcefield charges were assigned prior to conformation generation. A 20 kcal/mol energy cutoff was used to thoroughly sample conformational space, chiral inversion was not permitted, but rotation around amide bonds was allowed. The conformers were aligned by superposing the backbone atoms of the cyclic tetrapeptide prior to visual inspection of low energy structures.
26. Crystallographic data for compound 12 has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 728552. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif Author P.J.C. determined the X-ray strucutre of 12.