Bioorganic & Medicinal Chemistry Letters 12 (2002) 3337–3339
3-Hydroxy-4-methyl-5-pentyl-2-iminopyrrolidine: A Potent and
Highly Selective Inducible Nitric Oxide Synthase Inhibitor
Sofya Tsymbalov,a Timothy J. Hagen,a William M. Moore,b Gina M. Jerome,b
Jane R. Connor,b Pamela T. Manning,b Barnett S. Pitzelea and E. Ann Hallinana,*
aDepartment of Discovery Medicinal Chemistry, Pharmacia, 4901 Searle Parkway, Skokie, IL 60077, USA
bDepartment of Discovery Pharmacology, 800 North Lindbergh Boulevard, St. Louis, MO 63167, USA
Received 17 May 2002; accepted 7 August 2002
Abstract—(3S,4S,5R)-2-Imino-4-methyl-5-pentyl-3-pyrrolidinol hydrochloride (1) is a potent inducible nitric oxide synthase (i-
NOS) inhibitor that has three times the selectivity of its parent, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine hydrochloride (2).
# 2002 Published by Elsevier Science Ltd.
Selective inducible nitric oxide synthase (i-NOS) inhibi-
tors have therapeutic potential for the treatment of dis-
eases mediated by the overproduction of nitric oxide
(NO). Three isozymes of NOS have been identified and
characterized.1 Under normal physiological conditions,
the constitutive forms of NOS generate low, transient
levels of NO in response to increases in intracellular
calcium concentrations. NO regulates a variety of cel-
lular processes, among them vascular tone, platelet
aggregation, and immune response. NOS catalyzes a
five electron transfer during a heme-based oxidation of
l-arginine generating NO and citrulline. Elevated levels
of NO due to upregulation of the induced isoform,
i-NOS, and the resulting NO-derived metabolites, cause
cellular cytotoxicity and tissue damage and are thought
to contribute to the pathophysiology of a number of
human diseases.2 Selective iNOS inhibitors have been
shown to suppress the increase in plasma nitrites and/or
paw swelling associated with the overproduction of NO
in animal models of acute and chronic inflammation
including non-lethal endotoxemia,3 carrageenan-
induced paw edema4,5 and adjuvant-induced arthritis.6
A key intermediate in the synthesis of 1 was lactam 7.
Alternate routes to 77 were explored as the chromato-
graphic separation of the cis and trans isomers could
not be achieved unless a chiral stationary phase was
used. Initially, reduction of the 3,4-unsaturated lactam 6
as illustrated in Scheme 1 was investigated. To generate
6, the Boc-lactam 4 was treated with base and the anion
was quenched with phenylselenyl chloride. The phe-
nylselenide 5 was oxidized and eliminated in the pre-
sence of hydrogen peroxide. With 6 in hand, the cis-
lactam 7 was generated by the reduction of the olefin
.
with NaBH4 in the presence of NiCl2 6H2O.
The hydroxyl group was introduced using the same anion
chemistry that generated the phenylselenide. The addition
of HMPA to LiHMDS was necessary to obtain the
desired ring oxidation with (10-camphorsulfonyl)-
oxaziridine.8 To obtain 8, the precursor to 1 and 13,
(1S)-(10-camphorsulfonyl)oxaziridine was used as the
electrophile. Once the Boc group was removed by TFA
to obtain 9, the hydroxyl group was protected as a t-
butyldimethylsilylether (10). The iminoether (11) was
synthesized as described earlier.7 Amidine (12) was gen-
erated using ammonia in methanol. Removal of the silyl
group and protonation of the amidine was achieved
with aqueous HCl. Purification on a YMC ODS AQ
cis-4-Methyl-5-pentyl-iminopyrroldine (2)7 has been
reported to be a selective and potent i-NOS inhibitor. In
order to identify more potent and more selective i-NOS
inhibitors, we have investigated the effects of 3-hydro-
xylation (1) of the iminopyrrolidine ring (structures 1
and 2 are shown below).
*Corresponding author. Tel.: +1-847-982-7753; fax: +1-847-982-
7103; e-mail: ann.hallinan@pharmacia.com
0960-894X/02/$ - see front matter # 2002 Published by Elsevier Science Ltd.
PII: S0960-894X(02)00686-8
Tsymbalov, Sofya
