3042 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 18
Brief Articles
the SO2Me moiety was replaced by an azido substituent,
in the active site of human COX-2 showed a similar
interaction between the azido group and the COX-2
secondary pocket amino acid residues similar to that
observed for the pyrazole 13 (see Figure 5). The inter-
molecular energy between the ligand 17 and the enzyme
was -49.6 kcal/mol with the electrostatic component
comprising 5.8% of the total energy. In contrast, the
rofecoxib (4) docked complex showed an intermolecular
energy of -42.16 kcal/mol where only 1.2% was due to
an electrostatic component. The higher electrostatic
component for the azido compound 17 (5.8%), relative
to that for rofecoxib 4 (1.2%), is attributed to the fact
that the MeSO2 moiety present in rofecoxib undergoes
H-bonding to the imidazole NH of Hist90 in the second-
ary pocket. In contrast, the azido moiety in 17 undergoes
an electrostatic interaction with Arg513 in the secondary
COX-2 pocket. The lower contribution of the electro-
static energy to the total intermolecular energy in the
case of the furanone 17, relative to the pyrazole 13, can
be attributed to the observed hydrogen bonding interac-
tion between the O-atom of the CdO in the furanone
structure and residues lining the primary COX-2 chan-
nel, particularly Arg120. The azido analogue of refocoxib
17 exhibited a potent and selective inhibition of COX-2
(COX-2 IC50 ) 0.196 µM; COX-1 IC50 ) 159.7 µM; SI ≈
812). The molecular volumes of the selective COX-2
inhibitors 13 (279.4 Å3) and 17 (242.1 Å3) are moderately
smaller than that for the selective COX-2 inhibitors
celecoxib (298.4 Å3) and rofecoxib (262.5 Å3).
Refer en ces
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Con clu sion s
In conclusion, the dipolar azido group is a bioisostere
of the SO2NH2 and SO2Me hydrogen-bonding pharma-
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and the azido analogues 13 and 17 may be useful
biochemical agents for photoaffinity labeling of the
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Cyclooxygen a se In h ibition Stu d ies. All compounds de-
scribed herein were tested for their ability to inhibit COX-1
and COX-2 using a COX-(ovine) inhibitor screening kit (catalog
no. 560101, Cayman Chemical, Ann Arbor, MI) using the
method previously reported.4
An tiin flam m ator y Assay. The test compounds were evalu-
ated using the in vivo rat carrageenan-induced foot paw edema
model reported previously.20
An a lgesic Assa y. Analgesic activity was determined using
the 4% sodium chloride-induced writhing (abdominal constric-
tion) assay as described previously.21
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Prog. Med. Chem. 1999, 36, 201-234.
Ack n ow led gm en t. We are grateful to the Canadian
Institutes of Health Research (Grant MOP-14712) for
financial support of this research and to C.-A. McEwen
for technical assistance in performing the antiinflam-
matory and analgesic assays.
(19) Chan, C.-C.; et al. Rofecoxib [Vioxx, MK-0966; 4-(4′-Methylsul-
fonylphenyl)-3-phenyl-2-(5H)-furanone]: A potent and orally
active cyclooxygenase-2 inhibitor. Pharmacological and biochemi-
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(20) Kumar, P.; Knaus, E. E. Synthesis and antiinflammatory activity
of N-substituted-dihydropyridylacetic acids, esters and amides.
Drug Des. Delivery 1987, 2, 145-149.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of compounds 7-13 (Scheme 1)
and 15-17 (Scheme 2) and their IR and NMR (1H, 13C, 19F)
spectroscopic data. This material is available free of charge
on the Internet at http://pubs.acs.org.
(21) Buolamwini, J . K.; Knaus, E. E. Synthesis and antinociceptive
activity of 4-pyridyl and -dihydropyridyl analogues of meperidine
and ketobemidone. Drug Des. Delivery 1990, 7, 19-31.
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