Receptor antagonist libraries

Pollard et alP from Merck required both enantiomers of 3,5-bistrifluoro-methylphenyl ethanol since the (R)-enantiomer can be incorporated into Merck s orally active NKl receptor antagonist for the treatment of chemotherapy induced emesis, while the (5)-enantiomer is used as a chiral synthon for a number of antagonists which the same company currently have under clinical evaluation. Using proteins from a library of commercially available alcohol dehydrogenases both enantiomers were obtained with ees of 99% (Figure 1.40). 

Fig. 1.14. Kappa ( ) opioid receptor antagonist optimization library (reprinted ( adapted or in part ) with permission from Journal of the American Chemical Society. Copyright 1999 American Chemical Society).

Peptides complementary to the surface of Ab-2 (which acts as a receptor bioisostere) are selected from a peptide library (Lam et al., 1991 Houghten et al., 1991) using molecular immunology detection methods. Such peptides are expected to be receptor antagonists or agonists (Scott and Smith, 1990). 

NK3 antagonists design, svnthesis, binding to NK receptors solution, library [247 ... 

Neurokinin NK3 receptor antagonist and MMP Collagenase-1 inhibitor from orthogonal sets of 1600 member amide/ester library... 

Yanofsky SD, Baldwin DN, Butler JH, et al., High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries, Proc. Natl. Acad. Sci. USA, 93 7381-7386, 1996. 

Scheme 2 A pharmacophore-focused piperidine library designed from known NOP receptor antagonists. Blue, hydrophobic group Green, linker Orange Core Ring Red Fl-bond donor/acceptor...

The strategy is well illustrated by an example in which non-peptidic urotensin II receptor antagonists were identified based on the 11-amino acid cyclic peptide urotensin-II. " The SAR of urotensin-II was evaluated by truncation libraries and Ala and D-amino acid scans. These libraries revealed that the residues WKY are key for peptide function and lead to a 200-fold less active cyclic hexapeptide Ac-CFwKYC-NH2 containing a D-amino acid. D-configuration amino acids stabilise the formation... 

Other p-receptor antagonists have been identified from combinatorial libraries (seebelow). 

XIV. IDENTIFICATION OF RECEPTOR. ANTAGONISTS FOR CHEMOKINE RECEPTOR AND BRADYKININ-I BY SCREENING A ISO.OOO-MEMBER COMBINATORIAL LIBRARY... 

---