Letters
(7) Lassen, L. H.; Haderslev, P. A.; Jacobsen, V. B.; Iversen, H. K.;
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5567
(16) Prepared in one step from commercially available D-allylglycine:
Neuberger, A.; Tait, G. H. Synthesis of L-aspartic â-semialdehyde.
J. Chem. Soc. 1962, 3963-3968.
Sperling, B.; Olesen, J. CGRP may play a causative role in migraine.
Cephalalgia 2002, 22, 54-61.
(8) (a) Doods, H. Development of CGRP antagonists for the treatment
of migraine. Curr. Opin. InVest. Drugs 2001, 2, 1261-1268. (b)
Edvinsson, L. New therapeutic target in primary headachessblocking
the CGRP receptor. Expert Opin. Ther. Targets 2003, 7, 377-383.
(9) (a) Olesen, J.; Diener, H.-C.; Husstedt, I. W.; Goadsby, P. J.; Hall,
D.; Meier, U.; Pollentier, S.; Lesko, L. Calcitonin gene-related peptide
receptor antagonist BIBN 4096 BS for the acute treatment of
migraine. N. Engl. J. Med. 2004, 350, 1104-1110. (b) Doods, H.;
Hallermayer, G.; Wu, D.; Entzeroth, M.; Rudolf, K.; Engel, W.;
Eberlein, W. Pharmacological profile of BIBN4096BS, the first
selective small molecule CGRP antagonist. Br. J. Pharmacol. 2000,
129, 420-423.
(10) Shaw, A. W.; Paone, D. V.; Nguyen, D. N.; Stump, C. A.; Burgey,
C. S.; Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.; Kane, S. A.;
Koblan, K. S.; Graham, S. L.; Vacca, J. V.; Williams, T. M.
Caprolactams as potent CGRP receptor antagonists for the treatment
of migraine. Bioorg. Med. Chem. Lett. 2007, 17, 4795-4798.
(11) (a) Rudolf, K.; Eberlein, W.; Wolfhard, E.; Pieper, H.; Entzeroth,
M.; Hallermayer, G.; Doods, H. Development of human calcitonin
gene-related peptide (CGRP) receptor antagonists. 1. Potent and
selective small molecule CGRP antagonists. 1-[N2-[3,5-Dibromo-N-
[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-
D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)piperazine: the first CGRP antago-
nist for clinical trials in acute migraine. J. Med. Chem. 2005, 48,
5921-5931. (b) Bondensgaard, K.; Ankersen, M.; Thogersen, H.;
Hansen, B. S.; Wulff, B. S.; Bywater, R. P. Recognition of privileged
structures by G-protein coupled receptors. J. Med. Chem. 2004, 47,
888-899. (c) Patchett, A. A.; Nargund, R. P. Privileged structuress
an update. Annu. Rep. Med. Chem. 2000, 35, 289-298.
(12) For assay details, see Supporting Information or the following: Bell,
I. M.; Graham, S. L.; Williams, T. M.; Stump, C. A. Preparation of
benzodiazepine spirohydantoin CGRP receptor antagonists. WO 2004/
087649.
(13) Burgey, C. S.; Stump, C. A.; Nguyen, D. N.; Deng, J. Z.; Quigley,
A. G.; Norton, B. R.; Bell, I. M.; Mosser, S. D.; Salvatore, C. A.;
Rutledge, R. Z.; Kane, S. A.; Koblan, K. S.; Vacca, J. P.; Graham,
S. L.; Williams, T. M. Benzodiazepine calcitonin gene-related peptide
(CGRP) receptor antagonists: optimization of the 4-substituted
piperidine. Bioorg. Med. Chem. Lett. 2006, 16, 5052-5056.
(14) Compounds with serum shifted potencies in the range of that of 4
were determined by our rhesus pharmacodynamic assay to require
high plasma levels to achieve full efficacy.
(17) (a) Trnka, T. M.; Grubbs, R. H. The development of L2X2RudCHR
olefin metathesis catalysts: an organometallic success story. Acc.
Chem. Res. 2001, 34, 18-29. (b) Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Synthesis and reactivity of a new generation of
ruthenium-based olefin metathesis catalysts coordinated with 1,3-
dimesityl-4,5-dihydroimidazol-2-ylidene ligands. Org. Lett. 1999, 1,
953-956.
(18) During the course of this work, RCM of vinyl chlorides and
fluorides were disclosed. (a) For vinyl chloride RCM: Chao, W.;
Weinreb, S. M. The first examples of ring-closing olefin metathesis
of vinyl chlorides. Org. Lett. 2003, 5, 2505-2507. (b) For vinyl
fluoride RCM: Salim, S. S.; Bellingham, R. K.; Satcharoen, V.;
Brown, R. C. D. Synthesis of heterocycles and carbocyclic
fluoro-olefins by ring-closing metathesis. Org. Lett. 2003, 5, 3403-
3406.
(19) Isolated yield of RCM product. 15% starting material also was
recovered and recycled.
(20) For resynthesis of particularly promising analogs, the order of the
RCM and Suzuki steps was inverted, providing greatly improved
yields for the styrene RCM (60-70%).
(21) We had previously shown that in this series the trans isomers were
uniformly more potent than the cis, often by >20-fold (see ref 10).
Relative stereochemistry was determined by proton NMR analysis,
and absolute stereochemistry was assigned on the basis of the known
chirality of commercially available, enantiomerically pure starting
materials.
(22) This was demonstrated in a previous series: Williams, T. M.; Stump,
C. A.; Nguyen, D. N.; Quigley, A. G.; Bell, I. M.; Gallicchio, S. N.;
Zartman, C. B.; Wan, B.-L.; Della Penna, K.; Kunapuli, P.; Kane,
S. A.; Koblan, K. S.; Mosser, S. D.; Rutledge, R. Z.; Salvatore, C.;
Fay, J. F.; Vacca, J. P.; Graham, S. L. Non-peptide calcitonin gene-
related peptide receptor antagonists from a benzodiazepinone lead.
Bioorg. Med. Chem. Lett. 2006, 16, 2595-2598.
(23) Hershey, J. C.; Corcoran, H. A.; Baskin, E. P.; Salvatore, C. A.;
Mosser, S.; Williams, T. M.; Koblan, K. S.; Hargreaves, R.; Kane,
S. A. Investigation of the species selectivity of a nonpeptide CGRP
receptor antagonist using a novel pharmacodynamic assay. Regul.
Pept. 2005, 127, 71-77.
(24) Ho, T. W.; Mannix, L.; Fan, X.; Assaid, C.; Furtek, C.; Jones, C.;
Lines, C.; Rapoport, A. A randomized controlled trial of an oral
CGRP antagonist, MK-0974, in the treatment of migraine. Neurology,
in press.
(15) Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Miyamoto,
S.; Koike, H.; Iijima, Y.; Oizumi, K.; Matsushita, Y.; Hata, T.
Angiotensin-converting enzyme inhibitors. 2. Perhydroazepin-2-one
derivatives. J. Med. Chem. 1988, 31, 422-428.
JM070668P