J. Med. Chem. 2005, 48, 7517-7519
7517
Chart 1
Discovery of a Potent, Orally Available,
and Isoform-Selective Retinoic Acid â2
Receptor Agonist
Birgitte W. Lund,† Fabrice Piu,‡
Natalie K. Gauthier,‡ Anne Eeg,† Erika Currier,‡
Vladimir Sherbukhin,† Mark R. Brann,‡
Uli Hacksell,‡ and Roger Olsson*,†
ACADIA Pharmaceuticals AB, Medeon Science Park,
S-205 12 Malmo¨, Sweden, and ACADIA Pharmaceuticals
Inc., 3911 Sorrento Valley Blvd.,
San Diego, California 92121
Received September 9, 2005
Here we report on the discovery of the first ligand that
discriminates between nuclear receptor isoforms having
identical ligand binding domains. We also report on a
hit to lead optimization effort transforming a lipophilic,
poorly soluble hit into a more potent RAR agonist with
retained â2 selectivity and greatly improved physio-
chemical properties.
The RARâ2 receptor was screened in intact cell uHTS
format against a chemical library of over 160 000 small
molecule organic compounds using a functional R-SAT
assay.7 The confirmed RARâ2 receptor hits were profiled
against RARâ1 and the remaining of RARs (R and γ)
and RXRs (R, â, and γ) receptor subtypes. 4′-Octyl-4-
biphenylcarboxylic acid, AC-55649 (1g), was identified
as a novel retinoid-selective agonist with potency in
R-SAT of 100 nM at the RARâ2 receptor. Compound 1g
displays 100-fold selectivity for RARâ2 versus the other
retinoid receptors (Figure 1).
To further characterize 1g retinoid-like activities, its
ability to modulate transcriptional properties of retinoid
receptors was investigated. 1g was a potent and selec-
tive activator of RARâ2 transcriptional activity (pEC50
7.2, 71% eff).8 In addition, the activity of 1g was
confirmed by using a well-established in vitro system
commonly used to assess retinoid activity (inhibition of
proliferation of the breast cancer cell line MCF-7),8 and
nonselective toxic effects were ruled out by a study of
DNA synthesis measuring 3H thymidine incorporation.9
To establish the SAR of the 4′-alkyl chain length of
1g, commercially available analogues 1a-h with 2-9
carbons in the 4′-alkyl chain were studied (Table 1).
While a number of three carbons or less in the alkyls
chain did not result in any activity, the butyl, pentyl,
and hexyl analogue were potent but not efficacious.
Increasing the number of carbons in the alkyl chain
stepwise from 6 to 9 increased the efficacy. Thus, the
octyl and the nonyl chain analogues 1g and 1h displayed
full agonist activity. In addition, 1h showed an increased
potency at the RARâ1 isoform compared to 1g.
Abstract: 4′-Octyl-4-biphenylcarboxylic acid (1g, AC-55649)
was identified as a highly isoform-selective agonist at the
human RARâ2 receptor in a functional intact cell-based
screening assay. The subsequent hit to lead optimization
transformed the lipophilic, poorly soluble hit into a more potent
and orally available compound (2, AC-261066) with retained
â2 selectivity and greatly improved physiochemical properties.
Being an isoform-selective RARâ2 receptor agonist that dis-
criminates between nuclear receptor isoforms having identical
ligand binding domains, 2 will be useful as a pharmacological
research tool but also a valuable starting point for drug
development.
Isoform-selective retinoic acid receptor (RAR) agonists
are of potential use for the treatment of cancer and other
hyperproliferative disorders. Currently, several nonse-
lective retinoids are marketed or in clinical trials for
cancer therapy (e.g. Tretinoin (all-trans-retinoic acid,
ATRA) (Chart 1)). However, owing to their nonselective
profile, severe side effects have been observed during
chronic administration of these compounds.1
The biological effects of retinoids are mediated by two
classes of nuclear receptors, predominately in the form
of heterodimers, RARs and the retinoid X receptors
(RXRs), each of which contain three subtypes classified
as R, â, and γ.2 RARγ is associated with skin, bone, and
teratogenic toxicity, and RARR with triglyceride eleva-
tion. Thus, substantial toxicity may be avoided with a
selective RARâ ligand.3 The RARâ subtype consists of
four known isoforms generated from two promoters P1
(RARâ1 and RARâ3) and P2 (RARâ2 and RARâ4).4 Each
of the RARâ isoforms displays unique expression pat-
terns in the developing embryo and the adult, suggest-
ing specific, nonoverlapping physiological functions.4,5
For example RARâ2 has been suggested to exert an
isoform-specific suppressive effect of tumors in humans.6
Finding RARâ isoform-selective ligands constitutes a
challenging endeavor since the ligand binding domains
of the isoforms are identical. The variation between the
isoforms is located within the proximal N-terminus,
which encompasses the ligand-independent activation
domain (AF-1).
To improve the physicochemical properties of 1g, a
compound developed in the context of liquid crystals,11
a hit to lead optimization effort was initiated. Four
building blocks were combined (Chart 1): branched
alkyl and heteroalkyl groups of different chain lengths
(BB1); substituted aromatic and hetero aromatic rings
(BB2 and BB3); esters, amides, and carboxylic acid
bioisosteres, e.g. tetrazoles and sulfonamides (BB4).
* To whom correspondence should be addressed. Phone:
+46406013400. Fax: +46406013405. E-mail: roger@acadia-pharm-
.com.
† ACADIA Pharmaceuticals AB.
‡ ACADIA Pharmaceuticals Inc.
10.1021/jm050891r CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/04/2005
Lund, Birgitte W.
