3-(1H-Pyrrol-1-yl)-2-oxazolidinones as reversible, highly potent, and selective inhibitors of monoamine oxidase type A

Article abstract of DOI:10.1021/jm015578d

3-(1H-Pyrrol-1-yl)-2-oxazolidinones 1a-i have been synthesized as pyrrole analogues of toloxatone (Humoryl), an antidepressant agent belonging to the 3-phenyl-2-oxazolidi-none class, and their monoamine oxidase (MAO) type A and B inhibitory activities hav

Full text of DOI:10.1021/jm015578d

1
180
J . Med. Chem. 2002, 45, 1180-1183
3
-(1H-P yr r ol-1-yl)-2-oxa zolid in on es a s
Ch a r t 1. Irreversible (I) and Reversible (R) MAO
Inhibitors
Rever sible, High ly P oten t, a n d Selective
In h ibitor s of Mon oa m in e Oxid a se Typ e A
§
,§
§
Antonello Mai, Marino Artico,* Monica Esposito,
‡
#
†
Gianluca Sbardella, Silvio Massa, Olivia Befani,
Paola Turini, Valentina Giovannini, and
Bruno Mondov `ı *
†
†
,
†
Dipartimento di Studi Farmaceutici, Universit a` degli Studi
di Roma “La Sapienza”, P.le A. Moro 5, 00185 Roma, Italy,
Dipartimento di Scienze Farmaceutiche, Universita`
degli Studi di Salerno, via Ponte Don Melillo,
8
4084 Fisciano (SA), Italy, Dipartimento Farmaco Chimico
Tecnologico, Universit a` degli Studi di Siena, via Aldo Moro,
3100 Siena, Italy, and Dipartimento di Scienze
5
Biochimiche “A. Rossi Fanelli” and Centro di Biologia
Molecolare del CNR, Universit a` degli Studi di Roma
“La Sapienza”, P.le A. Moro 5, 00185 Roma, Italy
Received October 16, 2001
Abstr a ct: 3-(1H-Pyrrol-1-yl)-2-oxazolidinones 1a -i have been
synthesized as pyrrole analogues of toloxatone (Humoryl), an
antidepressant agent belonging to the 3-phenyl-2-oxazolidi-
none class, and their monoamine oxidase (MAO) type A and
B inhibitory activities have been evaluated. The majority of
1
a -i showed inhibitory activity against the A isoform of the
cypromine, and isocarboxazid, these MAOIs of second
generation present a more favorable tolerability profile,
and they have resulted in clinically effective agents in
many neuropsychiatric and affective disorders. Unfor-
tunately, they inhibit the MAO forms in an irreversible
manner, forming stable covalent adducts between the
enzyme and the drug or its reactive intermediate. This
irreversible way of action produces many important
limitations to the use of these compounds in therapy,
such as the loss of selectivity at high dosage and the
wide range of MAOI-drug and MAOI-food interac-
tions, mainly with sympathomimetic drugs or tyramine-
containing foods, that result in severe hypertensive
reactions. Other undesired side effects connected with
the use of irreversible MAOIs are central nervous effects
enzyme higher than that exerted against the MAO-B, the sole
exception being the (S)-5-aminomethylderivative 1d . (R)-5-
Methoxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone 1b, the most
potent among test derivatives, was 78-fold more potent than
toloxatone.
In tr od u ction . Monoamine oxidase (EC 1.4.3.4; MAO)
1
,2
is a FAD-containing enzyme
located in the outer
3
membrane of mitochondria. Two MAO isoforms, called
MAO-A and MAO-B, have been distinguished till now,
depending on different specificity for substrates, inhibi-
tor selectivity, and tissue distribution.4 The two forms
catalyze oxidative deamination of endogenous mono-
amines in the brain and the peripheral tissues, MAO-A
preferentially deaminating serotonin, epinephrine, and
nor-epinephrine and MAO-B mainly acting on dopa-
-6
(insomnia, irritability, agitation, hypomania, suppres-
7
mine, â-phenylethylamine, and benzylamine.
sion of REM sleep), cardiovascular disfunctions (ortho-
Due to the key role played by the two MAO forms in
the metabolism of monoamine neurotransmitters, MAO
inhibitors (MAOIs) can represent an useful tool for
treatment of several neurological diseases. In particular,
selective MAO-A inhibitors (e.g., clorgyline ) are used
as antidepressant and antianxiety drugs and are claimed
static hypotension), and sexual disturbances.1
2,13
The modern search in the anti-MAO field is now
directed toward the discovery of new reversible, third-
generation MAOIs that are as selective as possible to
one isoform of the enzyme. Reported reversible MAOIs
8
1
4
belong to the morpholino (moclobemide), piperidino
9
to protect neuronal cells against apoptosis, and selec-
1
5
16
(
brofaromine), 2-aminoethylcarboxamide (Ro 41-1049),
1
0
tive MAO-B inhibitors (e.g., L-deprenyl ) can be used
in the treatment of Parkinson’s disease either alone or
in combination with L-DOPA.11 In comparison with
older, nonselective MAOIs such as phenelzine, tranyl-
1
7
and 2-oxazolidinone series (toloxatone, cimoxatone,
befloxatone) (Chart 1). Toloxatone (Humoryl), a new
antidepressant agent marketed in France in 1985, is the
prototype of 3-phenyl-2-oxazolidinones, a class of MAOIs
highly active mainly against the A isoform of the
*
To whom correspondence should be sent. M.A.: tel and fax, +39
1
8-21
enzyme.
Chemical modifications performed on
0
0
6 446 2731; e-mail, marino.artico@uniroma1.it. B.M.: tel, +39 06 445
298; fax, +39 06 444 0062; e-mail, bruno.mondovi@uniroma1.it.
toloxatone have led to cimoxatone and, more recently,
to befloxatone, an anti-MAO agent active at nanomolar
§
Dipartimento di Studi Farmaceutici, Universit a` degli Studi di
Roma “La Sapienza”.
‡
concentrations and more A-selective than toloxatone
Universit a` degli Studi di Salerno.
Universit a` degli Studi di Siena.
Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Centro
#
22,23
(Chart 1).
However, such chemical manipulations
†
have regarded the substituent(s) located on the phenyl
ring at the N3 position or at the C5 methylene group of
di Biologia Molecolare del CNR, Universit a` degli Studi di Roma “La
Sapienza”.
1
0.1021/jm015578d CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/06/2002

Letters
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1181
the 2-oxazolidinone ring, while little or no attention has
been devoted to the replacement of phenyl with het-
eroaromatic rings.24
Pursuing our searches on synthesis and biological
evaluation of pyrrole-containing compounds active on
central nervous system,25-28 we planned the preparation
of 3-(1H-pyrrol-1-yl)-2-oxazolidinones 1a -i to be tested
as new anti-MAO agents. Derivatives 1a -i are char-
(R)- and (S)-5-azidomethyl derivatives 1b,g and 1c,h ,
respectively. 5-Aminomethyl- and 5-dimethylamino-
methyl-3-(1H-pyrrol-1yl)-2-oxazolidinones 1d ,i and 1e
were obtained by catalytic reduction of the appropriate
5-azidomethyl counterparts 1c,h with hydrogen (ami-
nomethyl) or with hydrogen and formaldehyde in excess
(dimethylaminomethyl compounds). A sample of toloxa-
tone was synthesized and used as reference drug in
biological tests of derivatives 1a -i.
Resu lts a n d Discu ssion . 5-Substituted-3-(1H-pyr-
rol-1-yl)-2-oxazolidinones 1a -i were evaluated for their
ability to inhibit MAO-A and MAO-B, in comparison
with toloxatone as reference drug. Inhibitory data of
befloxatone, a new toloxatone analogue actually in
2
2,23
phase III clinical trials, were also reported.
Bovine
brain mitochondria were used as the enzyme source and
were isolated according to the Basford method.30 Activi-
ties of MAO-A and MAO-B were determined by a
fluorimetric method with kynuramine as substrate.31
The Ki values against the two isoenzymatic MAO forms
and the A-selectivity (expressed as Ki MAO-B/Ki MAO-A
ratio) are summarized in Table 1.
acterized by the pyrrole moiety linked to the 2-oxazo-
lidinone ring through a N-N linkage, and bear different
substituents (hydroxy, methoxy, azido, amino, and
dimethylamino) at the C5-methyl of oxazolidinone por-
tion. Due to the presence of a chiral center at the C5
position of oxazolidinone moiety, both the enantiomeri-
cally pure (R and S) series of compounds were synthe-
sized and tested.
Test compounds have been divided into two groups
(A and B), according to their enantiomeric structure
(Table 1). All compounds except 1d showed inhibitory
activity against the A isoform of MAO enzyme higher
than that exerted against the MAO-B. Furthermore, all
derivatives displayed a reversible mode of action since
dialysis for 24 h in a cold room against 0.1 M potassium
phosphate buffer (pH 7.2) was able to restore 90-100%
of the enzyme activity.
Among compounds belonging to the A group, deriva-
tives 1a -c were the most active with concentration
values of MAO-A inhibitory activity in the nanomolar
range. In particular, in our experiments we found that
(R/S)-toloxatone and the related pyrrole analogue (ra-
cemic mixture of 1a and 1f) were equipotent as MAO-A
inhibitors, the latter being 6-fold less MAO-A selective
than the former. Furthermore, the assays performed on
the R (1a ) and S (1f) enantiomers showed 1a to possess
the best activity and selectivity.
Ch em ist r y. 1-(Phenylmethoxycarbonylamino)-1H-
2
9
pyrrole 2 was prepared from benzyl carbazate and 2,5-
dimethoxytetrahydrofuran in ethanol/acetic acid me-
dium as the starting material for the synthesis of title
derivatives. After treatment with n-butyllithium in
hexanes at -78 °C, the lithiated intermediate reacted
with enantiomerically pure glycidyl butyrate to furnish
directly, after spontaneous hydrolysis of the butyrate
function, the (R)- and (S)-5-hydroxymethyl-3-(1H-pyrrol-
1
-yl)-2-oxazolidinones 1a and 1f, depending on the R-
or S-glycidyl butyrate used, respectively. The alcohols
a ,f were converted into the corresponding methane-
1
sulfonates 3a ,b with methanesulfonyl chloride and
triethylamine, and these compounds were subjected to
nucleophilic displacement by sodium methoxide and
sodium azide to give (R)- and (S)-5-methoxymethyl and
Replacement of OH with other hydrophilic groups
(amino, azido, and dimethylamino) gave derivatives
Sch em e 1a
a
a: 2,5-Dimethoxytetrahydrofuran, AcOH, EtOH, ∆. b: AcOH, ∆. c: 2.5 M n-BuLi in hexanes, THF, -78 °C. d: (1) R-Glycidyl butyrate,
2) NH4Cl, rt. e: CH3SO2Cl, Et3N, CH2Cl2, rt. f: CH3ONa, CH3OH, rt. g: NaN3, DMF, 70 °C. h: H2, Pd/C, rt. i: H2, CH2O, Pd/C, rt. j:
1) S-Glycidyl butyrate, (2) NH4Cl, rt.
(
(

1
182 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6
Letters
Ta ble 1. Monoamine Oxidase Inhibitory Activity of
Compounds 1
Ack n ow led gm en t. This work was supported in part
by grants from CNR (project no. 98.01115.CT14 and
a
“target project on biotechnology”) and from MURST.
Su ppor tin g In for m ation Available: Chemical and physi-
cal data for compounds 1a -i are reported. This material is
available free of charge via the Internet at http://pubs.acs.org.
Ki values (µM)
A
compd formula (R or S)
R
MAO-A MAO-B selectivity
Refer en ces
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
g
h
A
A
A
A
A
B
B
B
B
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(R)
OH
OCH3
N3
NH2
N(CH3)2 40
OH
OCH3
N3
0.09
0.0049
0.2
9
50
200
4.4
140
2
23
24
34
2
15
0.22
100
10,200
1,000
(
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0.08
3.5
1.7
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9.6
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7
39.5
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2.5
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(
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c-e less potent and sometimes less selective than 1a .
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(
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1
(
correlates with the lipophilic nature of pyrrolyloxazoli-
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(
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(
(
(
(
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9
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(
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(
J M015578D