Bioorganic & Medicinal Chemistry Letters 11 (2001) 1±4
Imide and Lactam Derivatives of N-Benzylpyroglutamyl-
L-phenylalanine as VCAM/VLA-4 Antagonists
Jeerson W. Tilley,* Gerry Kaplan, Karen Rowan, Virginia Schwinge
and Barry Wolitzky
Roche Research Center, Homann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
Received 21 August 2000; accepted 18 September 2000
AbstractÐA series of imides and lactams derived from 4-amino-N-benzylpyroglutamyl-l-phenylalanine was prepared and
evaluated for activity as VCAM/VLA-4 antagonists. Imides were more potent than the corresponding lactams; several had
subnanomolar IC50s in an ELISA based assay and were also highly eective at blocking VLA-4 expressing Ramos cell binding to
VCAM coated plates. # 2000 Elsevier Science Ltd. All rights reserved.
The integrin VLA-4, a4-b1, is expressed on a variety of
lympocytes including B-cells, T-cells, basophils and
eosinophils and is involved in modulating tracking,
activation and survival of these cell types.1 Because of
its potentially key role in regulating the in¯ammatory
process, there is currently a great deal of interest in dis-
covering compounds capable of interfering with the
interaction of VLA-4 with its cognate receptor, VCAM.
Such compounds are being considered for clinical
trials in asthma,2 multiple sclerosis,3 and rheumatoid
arthritis.4
carbonyl would prefer to be out of conjugation, rather
than co-planar as demanded by the proposed cyclic
structures, our limited understanding of the details of
the SAR of phenylalanine derived VCAM/VLA-4
antagonists prompted us to carry out the investigation
described below. In this work we show that appropriate
imides 2 are nearly equipotent with the amide 1 whereas
the corresponding lactam derivatives 3 are several-fold
less potent.
We have previously reported the identi®cation of a ser-
ies of N-benzylpyroglutamyl 4-substituted-l-phenylala-
nine analogues that showed good potency as VCAM/
VLA-4 antagonists in both ELISA and cell based assay
formats.5 Among the most potent compounds were
those substituted by a benzoylamino group which
incorporated both an ortho substituent and at least one
electron withdrawing group such as 1. As part of an
eort to improve the pharmacokinetics of this class of
molecule, we sought to investigate whether elimination
of the para-amide NH- through incorporation of the
nitrogen atom into a cyclic imide or lactam ring to give
2 or 3, respectively, would be feasible.
The preparation of the imide derivatives is shown in
Scheme 1 starting from Na-Boc-4-Fmoc-aminophenyl-
alanine 4. Benzyl ester formation, cleavage of the Boc
group, coupling with N-benzyl pyroglutamic acid and
cleavage of the Fmoc group proceeded without incident
to give the amine 5 despite the low solubility of the
Fmoc containing intermediates. Formation of the imi-
des was generally eected by treatment of 5 with an
excess of the appropriate cyclic anhydride in the pre-
sence of excess carbonyl diimidazole. After stirring
overnight, the reaction mixtures were concentrated, the
residues dissolved in acetic acid and applied directly to a
C-18 RP-HPLC column eluting with acetonitrile±water.
While we recognized that the requirement for ortho-
substituents in compounds related to 1 suggested that
the p-system of the aromatic ring and the amide
*Corresponding author. Tel.: +1-973-235-4660; fax: +1-973-235-
6084; e-mail: jeerson.tilley@roche.com
0960-894X/01/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00582-5