Novel CGRP receptor antagonists through a design strategy of target simplification with addition of molecular flexibility

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 19, 2009, Pages 5787-5790

  Wood, Michael R ^a   Schirripa, Kathy M ^a   Kim, June J ^a   Quigley, Amy G ^a   Stump, Craig A ^a   Bell, Ian M ^a   Bednar, Rodney A ^a   Fay, John F ^a   Bruno, Joseph G ^a   Moore, Eric L ^a   Mosser, Scott D ^a   Roller, Shane ^a   Salvatore, Christopher A ^a   Kane, Stefanie A ^a   Vacca, Joseph P ^a   Selnick, Harold G ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Calcitonin gene related peptide; CGRP receptor antagonists; Migraine

Indexed keywords

ADRENOMEDULLIN RECEPTOR; CALCITONIN GENE RELATED PEPTIDE RECEPTOR ANTAGONIST; HYDANTOIN DERIVATIVE;

ARTICLE; BINDING AFFINITY; CHIRALITY; DRUG DESIGN; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; HUMAN; HUMAN CELL; STRUCTURE ACTIVITY RELATION;

ACETAMIDES; ANIMALS; CELL LINE; DRUG DESIGN; HUMANS; RATS; RECEPTORS, CALCITONIN GENE-RELATED PEPTIDE; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 69949108860     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.134     Document Type: Article

References (16)

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9. The benefits and rational for the introduction of the central quinoline linking the Eastern and Western portions of compound 1 will be the subject of a future paper, Stump, C.A., unpublished observations..
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11. Wood, M. R.; Kim, J. J.; McWherter, M.; Selnick, H. G.; Schirripa, K. PCT Int. Appl. WO 2008127584, 2008. All final compounds were characterized by 1H NMR, HPLC (purity >95%) and HRMS.
12. This preference for the (S) chirality also carried over to the n = 0 analogs of 4.
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14. 5- and 7-membered lactam analogs of 21a showed reduced CGRP receptor binding affinity.
15. 1H NMR, HPLC (purity >95%) and HRMS.
16. Functional activity determined by the inhibition of CGRP-induced cAMP production in HEK293 cells stably expressing human CLR/RAMP1. See Ref. 11 or 15 for experimental details.