DOI: 10.1002/anie.201007772
Atropisomerism
Atropisomerism in the Vaptan Class of Vasopressin Receptor Ligands:
The Active Conformation Recognized by the Receptor**
Hidetsugu Tabata, Jun Nakagomi, Daisuke Morizono, Tetsuta Oshitari, Hideyo Takahashi, and
Hideaki Natsugari*
Chiral compounds are generally thought of as compounds
with classical chiral centers (stereogenic elements, mostly
asymmetric carbon atoms). However, a nonplanar compound
may be chiral because it incorporates other (stereogenic)
elements, which comprise axes and planes. Axial chirality
(atropisomerism)[1] is caused by restricted rotation about a
single bond (axis), of which the most extensively studied is the
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2
ꢀ
sp sp axial chirality of biaryl compounds, as exemplified by
2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP). Aside
from biaryls, aryl amides and anilides, which exist in many
biologically active compounds as a part of the pharmaco-
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phore, also possess sp sp atropisomerism based on the aryl–
amide axis.[2] Although often overlooked, such atropisomer-
isms are latent in many organic molecules. It should be noted
that, even if the conformational change is too rapid for the
enantiomers to be isolated, target molecules such as receptors
and enzymes will recognize the active enantiomeric form to
exert biological activity.
Scheme 1. Vaptan class of vasopressin receptor ligands with the N-
benzoyl benzo-fused seven-membered-ring nitrogen heterocycles as
the scaffold structure: N-benzoyl-1,5-benzodiazepine derivatives (1–4),
mozavaptan (5), and lixivaptan (6).
Since the first discovery of a non-peptide arginine vaso-
pressin (AVP) V2 receptor antagonist (5; mozavaptan[3])
(Scheme 1), extensive research to find new ligands (antago-
nists and agonists) has been carried out.[4] To date, the
“vaptan” class of ligands (e.g., lixivaptan (6),[5] tolvaptan,[6]
and conivaptan[7]) has been developed as agents for the
treatment of hyponatremia, congestive heart failure, and so
forth. Interest is still growing in the search for new ligands and
their new indications as well as in determining the biological
role of the subtype V1a and V1b receptors. Many of the vaptan
class of drugs contain a preserved scaffold, that is, a benzo-
fused seven-membered-ring nitrogen heterocycle (e.g., ben-
zazepine, 1,4-benzodiazepine) linked through N-1 to a sub-
stituted p-amidobenzoyl group (e.g., 5, 6; Scheme 1). To the
best of our knowledge, however, regardless of the vast
number of studies performed in this field, there has been no
previous discussion of the atropisomeric structure around the
scaffold region (blue lines in the structures in Scheme 1),
which should play an important role in regard to its activity.
Herein, we report on the atropisomerism of the scaffold
region of the newly discovered AVP receptor ligands N-
benzoyl-1,5-benzodiazepines (1–4; Scheme 1), and the actual
active conformation recognized by the receptor, which was
clarified by freezing the conformation in the molecules.
At first sight, the presence of chirality may often be
overlooked, although the cis and trans rotamers[8] around the
ꢀ
=
N C( O) bond can be envisioned. However, a careful survey
[*] H. Tabata, J. Nakagomi, Dr. T. Oshitari, Prof. Dr. H. Takahashi,
Prof. Dr. H. Natsugari
of the chemical structure reveals that the region contains the
aS and aR atropisomeric structure[9] based on the Ar N(C
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=
School of Pharmaceutical Sciences
Teikyo University, 1091-1 Midori-ku
Sagamihara, Kanagawa 252-5195 (Japan)
Fax: (+81)426-85-3728
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O) (sp sp ) axis as well as the cis and trans rotamers. Thus,
theoretically the four stereoisomers (conformers) shown in
Scheme 2 may exist in the scaffold region. When the AVP
receptor binds to the ligand (e.g., 5, 6), it may recognize the
conformation of the region as suitable for binding. To gain an
insight into the actual active structure recognized by the
receptor we planned to separate the isomers by freezing the
conformation with a substituent at the ortho position (R) and
to examine the biological activities.
The 1,5-benzodiazepine nucleus was selected in this study
as the benzo-fused seven-membered-ring nitrogen hetero-
cycle. A few studies on AVP receptor ligand binding have
already been reported with this heterocycle. N-Benzoyl
derivatives of 1,5-benzodiazepin-2-ones (1–3) and the re-
E-mail: natsu@pharm.teikyo-u.ac.jp
D. Morizono
Tokyo Medical and Dental University
1-5-45 Yushima, Bunkyo-ku
Tokyo 113-8510 (Japan)
[**] We are grateful to Sagami Chemical Research Center for X-ray
analysis. This work was supported in part by the Japan Society for
the Promotion of Sciences by a Grant-in-Aid for Scientific Research
(C) (21590124) and a Grant-in-Aid for Young Scientists (B)
(21790025).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 3075 –3079
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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