Design and Synthesis of a Potent and Selective Triazolone-Based Peroxisome Proliferator-Activated Receptor α Agonist

Article abstract of DOI:10.1021/jm034173l

A new series of hPPARα agonists containing a 2,4-dihydro-3H-1,2,4-triazol-3-one (triazolone) core is described leading to the discovery of 5 (LY518674), a highly potent and selective PPARα agonist.

Full text of DOI:10.1021/jm034173l

J . Med. Chem. 2003, 46, 5121-5124
5121
Ch a r t 1. Structures of PPARR Agonists
Design a n d Syn th esis of a P oten t a n d
Selective Tr ia zolon e-Ba sed P er oxisom e
P r olifer a tor -Activa ted Recep tor r
Agon ist
Yanping Xu,† Daniel Mayhugh,† Ashraf Saeed,†
Xiaodong Wang,† Richard C. Thompson,†
Samuel J . Dominianni,† Raymond F. Kauffman,†
J aipal Singh,† J ames S. Bean,† William R. Bensch,†
Robert J . Barr,† J ohn Osborne,†
Chahrzad Montrose-Rafizadeh,† Richard W. Zink,†
Nathan P. Yumibe,† Naijia Huang,†
Debra Luffer-Atlas,† Deepa Rungta,‡
Dale E. Maise,‡ and Nathan B. Mantlo*,†
Lilly Research Laboratories, A Division of
Eli Lilly & Company, Lilly Corporate Center,
Indianapolis, Indiana 46285, and Ligand Pharmaceuticals,
10275 Science Center Drive, San Diego, California 92121
serum triglycerides and elicit increases in HDL-choles-
terol concentrations in humans.10 Several studies have
provided evidence that the hypolipidemic effect of this
class of drugs is caused by their agonist at the PPARR
receptor.12 In humans, the triglyceride-lowering effect
of fibrates is attributed to the activation of PPARR
which in turn effects an increase in lipoprotein lipase
gene expression and transrepression of apoC-III.13
PPARR-mediated elevation of HDL-cholesterol levels
observed with fibrates arises in part from the transcrip-
tional induction of the major HDL apolipoproteins,
apoA-I and apoA-II.13 Although fibrates are ligands for
the PPARR receptor, their activity and subtype selectiv-
ity is moderate. Therefore, a need exists for more potent
and subtype-selective human PPARR agonists. Such
agents could provide a superior clinical profile for the
therapeutic intervention of dyslipidemia. Recent disclo-
sures of highly selective and potent human PPARR
agonists attests to the heightened level of interest in
this arena. For example, GW9578 (3a )14a and GW7647
(3b) (Chart 1),14b selective hPPARR agonists, were found
to possess potent lipid-lowering activities in the choles-
terol/cholic acid-fed rat. Additionally, the Kyorin group
has reported a nonfibrate phenylpropanoic acid deriva-
tive (4)15 that is a potent hPPARR agonist in vitro with
selectivity for PPARR over PPARγ. As part of our
research directed toward the development of subtype-
selective modulators of the PPAR receptor family, we
have discovered a series of novel hPPARR agonists
possessing a 2,4-dihydro-3H-1,2,4-triazol-3-one (triazo-
lone) core that display potent and selective binding
affinity and functional activity on the hPPARR receptor
subtype and which exhibit highly potent in vivo efficacy
in a human apoA-I transgenic mouse model. This
account describes the synthesis and structure-activity
relationships of this series of hPPARR agonists which
culminated in the discovery of 5.
Received August 13, 2003
Abstr a ct: A new series of hPPARR agonists containing a 2,4-
dihydro-3H-1,2,4-triazol-3-one (triazolone) core is described
leading to the discovery of 5 (LY518674), a highly potent and
selective PPARR agonist.
In tr od u ction . Coronary heart disease (CHD) re-
mains the leading cause of death in the developed world
and is linked to a number of associated risk factors
including hypertriglyceridemia and hypercholester-
olemia. As members of the nuclear hormone receptor
superfamily of ligand-activated transcription factors, the
peroxisome proliferator-activated receptors (PPARs)
regulate a multitude of cellular processes including the
storage and catabolism of dietary fats and carbohy-
drates.1 Three mammalian PPAR isotypes have been
identified (PPARR, PPARγ, and PPARδ), and each
receptor displays distinct tissue-selective expression
patterns, ligand selectivity, and biological actions.2
Following activation of the receptor by ligand binding,
PPARs heterodimerize with the 9-cis-retinoic acid re-
ceptor (RXR).3 Upon binding of the heterodimer receptor
complex to peroxisome proliferator response elements
(PPREs) located in the regulatory regions of the target
genes and cofactor recruitment, gene transcription of
proteins involved in lipid metabolism and homeostasis
is stimulated.4,5 PPREs have been identified in the
promoter regions of several genes which encode proteins
involved in lipid and lipoprotein metabolism, such as
acyl-CoA oxidase (AOX),6 liver-fatty acid-binding protein
(L-FABP),7 apolipoprotein C-III (apo C-III),8 and li-
poprotein lipase (LPL).9
For several years, the fibrates (Figure 1, e.g., fenofi-
brate, 1) have been broadly utilized for the clinical
treatment of dyslipidemia and remain the current
treatment of choice for patients with severe hypertri-
glyceridemia.10,11 These agents can effectively decrease
Ch em istr y. Two different synthetic approaches were
utilized as shown in Scheme 1. Demethylation of ether
6b followed by alkylation with methyl or tert-butyl
bromoisobutyrate provided a diester which upon treat-
ment with hydrazine hydrate afforded hydrazide 7.
Installation of the R1 group using the appropriate
isocyanates afforded acylsemicarbazide 8. Ring con-
struction under KOH/MeOH led to the triazolone core
* Address correspondence to Nathan B. Mantlo, Lilly Research
Laboratories, Lilly Corporate Center, Indianapolis, IN 46285. Tel: 317-
433-0406, Fax: 317-277-2035. E-mail: nmantlo@lilly.com.
† Lilly Research Laboratories.
‡ Ligand Pharmaceuticals.
10.1021/jm034173l CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/18/2003

5122 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24
Letters
Sch em e 1a
Products can also be synthesized via intermediate 10
as shown in Scheme 1. Thus, methyl 3-methoxyphenyl-
propionate 6a was treated with hydrazine hydrate,
followed by the appropriate isocyanate to give acylsemi-
carbazides. Ring cyclization was achieved under KOH/
MeOH led to the triazolone core. Demethylation of 10
with BBr3 afforded the phenol, which was alkylated
using ethyl bromoisobutyrate to give triazolone ester 9b.
This latter intermediate provided acids 12 and 13 upon
alkaline hydrolysis.
Resu lts a n d Discu ssion . The 2,4-dihydro-3H-1,2,4-
triazol-3-ones were evaluated for in vitro potency and
selectivity by direct receptor binding (expressed as IC50
for displacement of radio-labeled reference compound)
as well as by cell-based assays to determine their
functional activity. The assays are transient transfection
assays in which the gene for the nuclear receptor(s), as
well as a plasmid containing a response element up-
stream of a luciferase cDNA, are transfected into CV-1
cells. Luciferase transcription occurs after activation of
the nuclear receptor(s) by binding of an agonist to the
receptor. For each compound, we determine an EC50 as
well as a percent maximum efficacy relative to a
reference compound.
The original screening lead 12 possessed a disubsti-
tuted triazolone tethered by a two-carbon atom alkyl
linker to a phenoxyisobutyrate (fibrate) moiety. This
compound possessed µM activity (EC50) on both hPPARR
and hPPARγ receptors. Investigation of the substituent
effects on the triazolone N2 and N4 positions on this two-
atom linker (n ) 2) lead series did not lead to improve-
ments in vitro (cf. 13). However a dramatic 450-fold
increase in hPPARR agonist activity (EC50) was ob-
served by homologating the linker length to three
carbons (see 15, n ) 3 vs 13, n ) 2). Compound 15
retains significant selectivity over hPPARγ and δ in
terms of both binding affinity and agonist activity. Upon
the basis of this result, efforts were concentrated on the
three carbon linker series. An early indication of the
critical requirement for substitution at the triazolone
N2 position within this series was provided by the
observation of a complete loss of binding affinity and
functional activity across all three receptor subtypes
when this position was unsubstituted (R2 ) H) or
substituted by small alkyl groups such as n-Pr, regard-
less of the substitutents on N4 (data not shown). In
general, an N2-benzyl substituent was consistent with
activity. Furthermore, activity was maintained or in-
creased by utilizing relatively nonpolar substituents at
the 3- or 4-positions of the benzyl moiety (c.f. 14, 15,
18, and 19). The chain-extended phenethyl analogue 16
afforded a more than 9-fold reduction in both hPPARR
binding affinity and transactivation potency relative to
compound 15, however remained devoid of cellular
activity at concentrations up to 10 µM on the other
PPAR receptor subtypes. The cyclohexylmethyl ana-
logue 17 resulted in a similar reduction in activity over
the substituted benzyl derivatives 14 or 15. Compound
18 (R2 ) p-tert-butylbenzyl, R1 ) Me) displayed the
greatest hPPARR functional potency (EC50 ) 2 nM) and
was >700-fold more selective for hPPARR over the other
subtypes from a functional perspective (EC50). Substitu-
ent effects at the N4 position were less pronounced
compared to those at the N2 position. For example,
a
Reagents and conditions: (a) BBr3, CH2Cl2, 0 °C; (b) BrC(Me)2-
CO2tBu, K2CO3, MgSO4, DMF, 75 °C; (c) hydrazine hydrate,
CH3OH, rt; (d) R1NCO, THF, rt; (e) KOH, CH3OH, reflux; (f)
CH3OH, H2SO4, rt; (g) R2Br or R2Cl, K2CO3, DMF, 45 °C; (h) 2N
NaOH, CH3OH, rt; (i) HBr/HOAC, rt; CH3OH, H2SO4, rt. (j) R1I,
or R1Br, K2CO3, DMF, 45 °C; (k) BrC(Me)2CO2Et, K2CO3, MgSO4,
DMF, 75 °C.
with concomitant hydrolysis of the methyl or tert-butyl
ester.16,17,18 The acid was re-esterified with methanol
and sulfuric acid. Triazolone 9a (R2 ) H) was employed
as a late stage intermediate for introduction of various
alkyl groups at the N2 position. Regioselective N2
alkylation of 9a occurred by treatment with appropriate
benzyl or alkyl halides in the presence of K2CO3 in
DMF.19 Final products 14-19 were prepared by ester
hydrolysis of the appropriately substituted ester inter-
mediate 9a . This method served a convergent approach
to the analogues that allowed us to explore the receptor
pocket at R2 region.
To explore various R1 groups exemplified by com-
pound 5, 20, and 21, an N4-dimethoxybenzyl (DMB)
group was employed on triazolone 9a as an acid-labile
protecting group. Using the same reaction sequence
described above, N4-2,4-DMB-protected triazolone 9 was
prepared from 2,4-dimethoxybenzyl isocynate. An acid-
mediated cleavage of the N4-2,4-DMB group was ac-
complished by using HBr/HOAc with concomitant ester
hydrolysis to afford the carboxylic acid 5. To explore
various R1 groups, acid 5 was re-esterified under Fisher
esterification conditions to afford the N4-unsubstituted
triazolone 11a . Ester 11a was regioselectively alkylated
at the triazolone N4 position by treatment with ap-
propriately substituted alkyl bromides in the presence
of K2CO3 in DMF to afford intermediate 11b.16 Saponi-
fication of the ester 11b provided the desired products
(20 and 21).

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24 5123
b
Ta ble 1. Binding IC50aand Cotransfection EC50 Datac on Human and PPAR Receptor Subtypes
hPPARRf hPPARγg
hPPARδf
no.
IC50 (nM)
EC50 (nM)d
IC50 (nM)
n.b.
EC50 (nM)
IC50 (nM)
EC50 (nM)d
2
24000 ( 290
13000 ( 260
340 ( 130
2200
n.a.
1900 ( 160
2600
n.b.
n.a.
e
e
3a
12
13
14
15
16
17
18
19
20
21
5
120 ( 11
550 ( 55
e
e
e
e
e
e
e
e
2800 ( 61
2900 ( 78
19 ( 2
16 ( 2
220 ( 19
250 ( 52
15 ( 1
12 ( 1
27 ( 2
960 ( 48
24 ( 3
31 ( 6
6200 ( 480
n.a.
2000 ( 220
1200 ( 120
1500 ( 200
880 ( 31
1700 ( 15
740 ( 70
4100 ( 330
n.b.
n.a.
3000 ( 19
n.a.
3000 ( 20
3000 ( 19
2900 ( 8
n.a.
6 ( 1
4900 ( 1000
6100 ( 720
1700 ( 120
520 ( 27
2700 ( 63
n.a.
2600 ( 47
1500 ( 130
2300 ( 80
n.a.
220 ( 15
56 ( 7
2 ( 0
4 ( 1
1700 ( 190
6100 ( 350
7900 ( 540
6500 ( 686
88 ( 26
2700 ( 36
42 ( 5
n.a.
n.a.
n.a.
n.a.
3800 ( 1000
a
b
Concentration of test compound required to displace 50% of tritiated ligand. Concentration of test compound which produced 50%
of the maximal reporter activity. c n ) 3-6; n.b. ) no binding; n.a. ) efficacy relative to control was less that 20% at 10 µΜ. Gal4-
hPPARR was used to eliminate interference by endogenous PPARγ receptors in CV-1 cells. e Not determined. f Tritium-labeled PPARR/
PPARδ agonist, 2-(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}phenoxy)-2-methylbutyric acid, was used as radioligand for generating
displacement curves and IC50 values. Tritium-labeled PPARγ agonist, 5-{4-[2-(methylpyridin-2-ylamino)ethoxy]benzyl}thiazolidine-2,4-
dione, was used as radioligand for generating displacement curves and IC50 values.
d
g
Ta ble 2. Efficacy in Human ApoA-I Transgenic Micea
compound 20 (R1 ) hydroxyethyl) suffered a minor loss
HDL-c elevation
triglycerides lowering
ED50 (mg/kg)
in hPPARR functional potency compared to compound
15; however, incorporation of an acetic acid moiety at
this position (21) resulted in a sharp loss in hPPARR
affinity and potency. The unsubstituted analogue 5 was
slightly less active on hPPARR (EC50 ) 42 nM) when
compared to the N4-propyl analogue 15 (EC50 ) 6 nM).
Triazolones 5 and 15 demonstrated sufficient potency
and selectivity for the hPPARR receptor over other
hPPAR isoforms to warrant further investigation.
Further selectivity of compounds 5 and 15 was
examined using a panel of nuclear transcription factors.
These compounds either failed to bind or displayed poor
affinity (Ki > 10 µM) to the retinoic acid receptor (RARR,
RARâ, RARγ), retinoic acid X receptor (RXRR, RXRâ,
RXRγ), glucocorticoid receptor, and thyroid receptor
(TRR and TRâ). Furthermore, cotransfection assays for
RARR and RXRR demonstrated a lack of agonist activity
for 5 and 15 at these receptors.
no. ED50 (mg/kg) max. (% increase)
1
5
15
110 ( 76
0.30 ( 0.1
0.70 ( 0.2
120 ( 15
210 ( 15
200 ( 17
79 ( 21
0.10 ( 0.04
0.50 ( 0.21
a
Dosed 7 days q.d. by gavage, serum parameters determined 3
h after the last dose. ED50s and maximal % increase in HDL-c
were obtained by nonlinear regression analysis of dose-response
curves.
oral bioavailability (>50%), 5 had higher exposure
following oral dosing and a longer plasma half-life than
compound 15 in both species. These pharmacokinetic
differences between 5 and compound 15 have been
attributed primarily to the higher clearance observed
for compound 15 in Beagle dogs and F344 rats.
In summary, we have identified a novel series of 2,4-
dihydro-3H-1,2,4-triazol-3-ones as potent and selective
hPPARR agonists. This work led to the discovery of
LY518674 (5), which has been selected for clinical
studies. A full account of the structure-activity rela-
tionships within this series will be published in due
course.
Triazolones 5 and 15, as well as fenofibrate 1, were
evaluated in human apoA-I transgenic mice for their
ability to alter serum triglyceride and HDL-cholesterol
levels. Introduction of the promoter and transgene for
human apolipoprotein A-I into the mouse represents
a more humanlike model in which PPARR agonists
cause induction, rather than repression, of apolipopro-
tein A-I, thus elevating serum HDL-cholesterol.20 Since
this mouse model relies on endogenous PPARR to
interact with the human apoA-1 promoter, the in vitro
activity at the murine PPARR receptor was deter-
mined.21 In cotransfection assays containing the murine
PPARR receptor, compounds 5 and 15 exhibited EC50
values of 1052 ( 30 and 390 ( 63 nM, respectively. After
oral administration once daily at 3 mg/kg for one week,
compound 5 produced a 208% elevation in HDL-
cholesterol (ED50 ) 0.3 mg/kg) and a 96% decrease in
serum triglycerides (ED50 ) 0.10 mg/kg), relative to
control levels. Compound 15 showed similar efficacy and
potency in this model. The ED50’s for both HDL-
cholesterol elevation and triglyceride reduction for 5 are
2-3 orders of magnitude more potent than the corre-
sponding values for fenofibrate 1. Pharmacokinetic
studies conducted in Beagle dogs and F344 rats with 5
and 15 indicated that while both compounds had good
Ack n ow led gm en t. The authors thank Don J ett for
technical support and Kelly Wheeler for assistance with
the preparation of this manuscript.
Su p p or tin g In for m a tion Ava ila ble: Comparative phar-
macokinetic data, experimental details for the binding assays,
cotransfection assays, and the synthetic procedures for inter-
mediates and final compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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A Ureido-Thioisobutyric Acid (GW9578) Is a Subtype-
Selective PPARR Agonist with Potent Lipid-Lowering Activity.
J M034173L