Bioorganic & Medicinal Chemistry Letters
Preparation of imidazoles as potent calcitonin gene-related peptide
(CGRP) antagonists
b
b
b
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George Tora a, , Andrew P. Degnan , Charles M. Conway , Walter A. Kostich , Carl D. Davis ,
Sokhom S. Pin b, Richard Schartman b, Cen Xu b, Kimberly A. Widmann b, John E. Macor b
Gene M. Dubowchik b
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a Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA
b Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Several new potent CGRP receptor antagonists have been prepared in which the amide bond of lead com-
pound 1 has been replaced by bioisosteric imidazole moieties. Substitution at N-1 of the imidazole was
optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of
the imidazole to form tetrahydroimidazo[1,5-a]pyrazine 43 gave substantially improved permeability.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 3 June 2013
Revised 26 July 2013
Accepted 5 August 2013
Available online 13 August 2013
Keywords:
CGRP receptor antagonists
CGRP
Migraine
Migraineurs
Imidazoles
Migraine is a common and debilitating primary headache which
can cause significant pain for hours or even days.1 Characterized by
a unilateral throbbing pain, migraine is often accompanied by one
or more of the following symptoms: nausea, vomiting, dizziness,
tingling or numbness in the face, visual disturbance, and extreme
sensitivity to light, touch and smell.2 Approximately 13% of the
US adult population (mostly women), experience migraines.3
Whereas the direct cost of medication and absenteeism from work
continue to rise,4 the economic consequence of migraines remains
largely unrecognized and underappreciated. Currently the triptans
are used as the standard of care. Triptans are selective 5-HT1B/1D
receptor agonists and are believed to act primarily by simple vaso-
constriction of cranial vessels, which are dilated during a migraine
attack.5 However, because the 5-HT1B/1D receptor agonists are non-
selective vasoconstrictors, triptans are associated with a number of
cardiovascular side effects and are contraindicated in patients with
hypertension or ischemic heart disease.1
has been shown clinically that administration of 4 structurally dif-
ferent CGRP receptor antagonists [BIBN4096BS (olcegepant), MK-
974 (telcagepant), MK-3207 and BI-44370] have aborted acute
migraine8 with a significant effect at the 2 h endpoint. Importantly,
BIBN4096BS (olcegepant) achieved efficacy without the cardiovas-
cular side effects associated with the use of triptans.9
Although BIBN4096BS provided a proof of concept for the treat-
ment of acute migraine headache with a CGRP receptor, it was
administered by intravenous infusion during clinical trials. Intranasal
medications for the treatment of migraine have recently received in-
creased attention, and our earlier letter disclosed our intranasal (IN)
development compound BMS-694153 (1),10 which had a number of
desirable properties to support its selection. However, it is important
to emphasize that a preference study has shown that most migraine
patients preferred oral tripan tablets to an intranasal formulation.11
Although intranasal tryptans have a rapid onset and good tolerability
profile, most patients cannot tolerate their unpleasant taste.12 There-
fore, we also sought to identify an orally active CGRP antagonist to
treat acute migraine headache.13
Calcitonin gene-related peptide (CGRP) is a 37-amino acid pep-
tide that belongs to a family of structurally related peptides includ-
ing adrenomedullin and amylin and has been strongly implicated
in the pathogenesis of migraine.6 Cranial CGRP levels are elevated
in patients with migraine, and in fact, infusion of CGRP has been
shown to trigger migraine attacks in migraineurs.7 Moreover, it
Although compound
1 exhibited excellent intranasal
bioavailability in rabbit (FIN = 55–59%), it did not exhibit significant
oral bioavailability in cynomolgus monkey or rat (Fpo 60.3%).
We hypothesized that the poor intrinsic permeability of
1
(PAMPA = 11 nm/s @ pH 7.4) was responsible for the poor oral
exposure. In order to improve the permeability of our molecules,
we targeted isosteric replacement of the amide (Fig. 1). However,
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Corresponding author. Tel.: +1 609 818 4972; fax: +1 609 818 3331.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.