N-aryl-oxazolidin-2-imine muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation

Article abstract of DOI:10.1021/jm801583j

A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogue

Full text of DOI:10.1021/jm801583j

2794
J. Med. Chem. 2009, 52, 2794–2798
N-Aryl-oxazolidin-2-imine Muscle Selective Androgen Receptor Modulators Enhance Potency
through Pharmacophore Reorientation†,4
Alexandra A. Nirschl,‡ Yan Zou,‡ Stanley R. Krystek, Jr.,*,§ James C. Sutton,‡,3 Ligaya M. Simpkins,‡ John A. Lupisella,|
Joyce E. Kuhns,| Ramakrishna Seethala,§ Rajasree Golla,§ Paul G. Sleph,| Blake C. Beehler,| Gary J. Grover,|,O Donald Egan,|
Aberra Fura, Viral P. Vyas, Yi-Xin Li,# John S. Sack,§ Kevin F. Kish,§ Yongmi An,§ James A. Bryson,§ Jack Z. Gougoutas,#
John DiMarco,# Robert Zahler,‡ Jacek Ostrowski,| and Lawrence G. Hamann*,‡
DiscoVery Chemistry, Molecular Biosciences, DiscoVery Biology, MAP DiscoVery, DiscoVery Analytical Sciences, Analytical Research &
DeVelopment, Bristol-Myers Squibb Research and DeVelopment, P.O. Box 5400, Princeton, New Jersey 08543-5400
ReceiVed December 15, 2008
A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained
during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among
the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and
functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class
showed good oral bioavailability and were highly active in a standard rodent pharmacological model.
Introduction
The search for alternatives to testosterone (Ta) and its
analogues to address a range of unmet medical needs from age-
related functional decline related to decreased T in aging men1,2
to muscle wasting conditions3 and cognitive disorders including
Alzheimer’s disease4 has been attracting greater attention from
the biomedical community. From the first disclosure of an orally
active nonsteroidal androgen nearly a decade ago,5 a growing
number of novel chemical structural motifs have emerged from
several groups.6-8 In connection with our long-standing interest
in identifying potent and muscle selective agonists of the
androgen receptor (AR), which might show clinical promise
for the treatment of age-related functional decline in elderly men,
we have continued to explore structure-activity and struc-
ture-selectivity relationships around our previously disclosed
bicyclohydantoin selective androgen receptor modulator (SARM)
scaffold.9,10 Our preclinical discovery program previously
identified BMS-564929 (Figure 1) as an orally active, highly
potent muscle SARM, and this compound is one of several
agents that have advanced to clinical studies.11-13 In our
subsequent efforts, we wished to maintain the hydroxy-
substituted [5,5] bicyclic scaffold for its optimal receptor binding
features but to make other modifications to the molecules that
might enhance pharmaceutics and/or formulation properties of
Figure 1. Bicyclic N-arylurea selective androgen receptor modulators.
the lead compound, including aqueous solubility.14 Recognizing
that subtle changes in nuclear receptor ligand structure and
binding motifs can lead to profound changes in phenotype, we
also hoped to broaden our understanding of factors governing
tissue selectivity through application of structural biology tools
to evaluate novel ligands.15 To that end, we set out to explore
C1 des-carbonyl analogues of our earlier bicyclohydantoins,
including both bridgehead and C1-alkylated imidazolidin-2-ones,
as they were envisioned to sterically and/or electronically block
possible metabolic oxidation at C1. In the course of chemical
syntheses of molecules in support of these investigations,14 side-
products were observed that led to the discovery of a confor-
mationally novel SARM scaffold. Subsequent targeted synthesis
of analogues sharing this novel architecture yielded compounds
that are among the most potent SARMs identified to date and
that possess moderately wide separation between muscle and
prostate activity in vivo.
†
The X-ray coordinates for the complex of compound 6c and androgen
receptor have been deposited to the Protein Data Bank, PDB ID code 3G0W.
4
The authors dedicate this paper to the memory of John DiMarco.
* To whom correspondence should be addressed. For S.R.K.: phone,
609-818-3914; fax, 609-818-3914; E-mail: stanley.krystek@bms.com; cur-
rent address, Research & Discovery, Bristol-Myers Squibb, P.O. Box 5400,
Princeton, NJ 08543. for L.G.H.: phone, 617-871-4374; E-mail,
lawrence.hamann@novartis.com; current address, Novartis Institutes for
Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139.
Chemistry
The first compounds in the present angularly configured series
of SARMs were discovered through isolation and characteriza-
tion of side products obtained in a cyclization sequence designed
to close the central ring of the aryl-substituted bicyclic scaffold.
Under the conditions we had previously employed to access
C1-trifluoromethyl-substituted analogues in the imidazolidin-
2-one series from hydroxy urea intermediates 414 (tBuOK, THF,
-78 °C, followed by pTsCl),16 followed by desilylation with
fluoride, we observed variable amounts of side products with
the same molecular mass as the expected N-cyclized products
5 (Scheme 1). The side products were rigorously characterized
‡
Discovery Chemistry.
Molecular Biosciences.
Discovery Biology.
§
|
MAP Discovery.
Discovery Analytical Sciences.
Current address: E-mail: james.sutton@novartis.com. Novartis Institutes
#
3
for Biomedical Research, 4560 Horton Street, Emeryville, CA 94608.
O
Current address: E-mail: garygrover@productsafetylabs.com. Product
Safety Laboratories, 2394 Route 130, Dayton, NJ 08810.
a Abbreviations: SARM: selective androgen receptor modulator; T:
testosterone; AR: androgen receptor; ER: estrogen receptor; PR: progest-
erone receptor; GR: glucocorticoid receptor; MR: mineralocorticoid receptor.
10.1021/jm801583j CCC: $40.75
2009 American Chemical Society
Published on Web 04/07/2009

N-Aryl-oxazolidin-2-imine Muscle SelectiVe AR Modulators
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2795
Scheme 1a
a Reagents and conditions: (a) KOt-Bu (2.5 equiv), p-Tos-Cl, THF, 0 °C (8-12%); (b) PPh3, CCl4, Et3N (11-77%); (c) TBAF, THF (26-83%); (d)
HF·py, THF, 0 °C to rt (45-92%).
Scheme 2a
prior to deprotection to give acylguanidine 13. A cyanoguanidine
analogue 15 was prepared in three steps from Boc-protected
diamine 14 by Boc removal, followed by treatment with
diphenyl cyanocarbonimidate and Hu¨nig’s base in a sealed tube
at 160 °C and subsequent desilylation with TBAF.
Biological Results and Discussion
Our initial discovery of side products in the synthetic step
to complete the heterobicyclic imidazolidin-2-one ring forma-
tion of earlier SARMs led us to first elucidate the structure
of these isomeric species and to then characterize the in vitro
pharmacological profile of these compounds. Much to our
surprise, the N-aryl imine prototype compound 6a exhibited
a Reagents and conditions: (a) 4 Å molecular sieves, MeOH, 0 °C;
both receptor binding (0.8 nM) and functional activity (4.8
BnNH2, NaCNBH3; (b) H2, Pd(OH)2/C, EtOH (55%, 2 steps); (c) 2-chloro-
nM) within the potency range of the corresponding bicyclo-
4-isocyanato-3-methylbenzonitrile, THF (82%); (d) TFA, CH2Cl2, NaHCO3
hydantoin clinical compound 1 and its descarbonyl analogue
2 (Table 1). This finding was particularly unexpected due to
the seemingly altered structural alignment of key pharma-
cophoric elements in the imine scaffold relative to the
imidazolone core and due to detailed analysis of binding
interactions of compound 1 obtained through an X-ray
cocrystal structure.11 Diastereomeric alcohol 6b was found
to have similar potency. A series of alkyl and haloalkyl
substitutions were then evaluated at C1 of the bicyclic
skeleton, as these groups had imparted potent activity and
favorable physical properties in the earlier series. While all
five compounds in this grouping (6c-6g) had very tight
binding affinity (Kis 200-700 pM), the compounds were
more differentiated in their agonist potencies in transcriptional
assays. The strongest correlation of structural features with
functional agonist potency in this series appears to be that
alignment of the hydroxyl and alkyl groups on the same face
of the puckered bicyclic scaffold is preferred, and this
parameter supersedes any direct impact of absolute config-
uration at the two steroecenters adjacent to the ring-fused
carbon. Several guanidine analogues were also prepared to
explore the effects of oxygen replacement. Unsubstituted
guanidine 11, as well as the N-methyl (12) and N-acyl (13)
versions and the transposed cyanoguanidine 15 exhibited AR
binding affinity within range of the parent 2. However, it is
interesting to note that none of these compounds showed
robust agonist activity in cellular assays but rather exhibited
a partial agonist (12, 13, 15) or antagonist (11) phenotype.
(100%); (e) HgCl2, THF, 55 °C (33%); (f) NaH, DMF, MeI (50%); (g)
HF·py, THF; (h) NaH, DMF, BrCN (32%).
Scheme 3a
a Reagents and conditions: (a) 15% TFA in CH2Cl2; (b) diphenyl
cyanocarbonimidate, DIPEA, sealed tube, 160 °C, 2 h; (c) TBAF, THF
(72%, 3 steps).
through extensive NMR experiments and X-ray crystallography,
revealing the O-cyclized Z-oxazolidin-2-imine products 6. Upon
biological testing of a prototype analogue in this O-cyclized
series, we were surprised to learn of the exquisite potency
exhibited by this alternative pharmacophoric arrangement.
Consequently, we optimized conditions to favor the O-cycliza-
tion pathway in order to generate other members of this series
to better understand the pharmacologic properties associated
with this alternative scaffold. We found that treatment of ureas
4 with Ph3P and NEt3 in CHCl3 provided O-cyclized Z-imine
compounds as the major products (sole products in the cases
where R′ in cyclization precursor 4 ) CF3) in moderate to good
yields.17 Desilylation of the secondary alcohols of the cyclization
products by use of either TBAF or HF/pyridine provided the
O-cyclized targets 6a-g.
Guanidine derivatives 11-13 were derived from aldehyde 7
(Scheme 2), beginning with a 2-step conversion to primary
amine 8. Reaction with 2-chloro-4-isocyanato-3-methylben-
zonitrile (prepared in one step via treatment with thiophosgene)
provided thiourea 9. Boc-deprotection and HgCl2-mediated
cyclization yielded the desired cyclic guanidine 10, which was
desilylated to provide 11, or alternatively N-methylated, fol-
lowed by desilylation to provide 12. A third analogue was
prepared from 10 by treatment with NaH and CNBr in DMF
Despite the potential for chemical instability of the oxazolidin-
2-imines at gut pH (we found 6c to be unstable in solution, 0.1
N HCl, 37 °C, 24 h, 0.41% remaining), we chose to advance
6c to rodent studies in order to evaluate the anabolic efficacy
and tissue selectivity. In a preliminary rat PK screen, 6c was
found to have a surprisingly high AUC (5800 nM × h after a
5 mg/kg po dose) considering its acid instability. In a subsequent
standard two week castrated rat model in recovery mode,18,19
once daily 6c exhibited a muscle ED50 of 0.9 µg/kg po and a

2796 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Nirschl et al.
Table 1. Androgen Receptor Binding (Ki) and Functional (EC50)
Potencyb
a Ar ) 2-chloro-3-methylbenzonitrile. b In vitro data are at least two
separate measurements, see ref 11 for detailed assay conditions. c IC50,
antagonist mode.
Figure 2. (A) X-ray cocrystal structure of 6c bound to the human
androgen receptor ligand binding domain at 2.0 Å resolution. There
are several hydrogen bonds (dashed lines) seen in the complex of 6c
and AR LBD: the CN group of 6c can form a hydrogen bond with
R752 at 2.81 Å; the CN group of 6c and a bound water molecule can
also form a hydrogen bond; the hydroxyl group of 6c can form a
hydrogen bond with N705 at 2.75 Å. (B) Superimposition of X-ray co
crystal structures of 1 and 6c. The protein backbone is displayed in
the orange ribbon. The C atoms of compound 6c are colored white,
and C atoms of compound 1 are colored green.
Table 2. Growth of Levator Ani Muscle and Prostate in Castrated Male
Rats
6c (mg/kg, po)
LA % intact ( SE
P % intact ( SE
0.00001
0.0001
0.001
0.01
0.03
0.1
21.0 ( 1.2
25.0 ( 2.73
59.0 ( 1.72
109.3 ( 9.02
103.5 ( 2.94
100.5 ( 2.85
103.9 ( 6.72
2.6 ( 0.54
3.6 ( 0.48
9.5 ( 1.05
38.8 ( 6.96
72.9 ( 8.2
103.0 ( 10.7
104.5 ( 5.2
0.3
ED50, µg/kg
0.9
210
14.3
420
anchoring contacts, and sufficient plasticity in the LBD exists
to accommodate maintaining a productive H-bond with T877
and/or N705 through the hydroxy group of 6c. There is also
a water molecule bound to the CN group of 6c that has not
been observed with our previous AR structures. This water
is analogous to that seen for progesterone bound to its
receptor. In addition, the CF3 moiety from 6c projects toward
helix 12 of AR, causing M895 to rearrange so as to create a
small cavity between W741 and helix 12. Interestingly, unlike
the highly tissue selective compound 1 but similar to that
seen with the native hormones T and DHT, 6c experiences
a bifurcated H-bond to both T877 and N705. It is not yet
clear whether the empirical correlation of this binding feature
to reduced tissue selectivity in vivo is mechanistically linked.
It is envisioned that with a larger collection of suitable tool
molecules of varying binding modes, a deeper understanding
of this relationship might be achieved.
TP ED50, µg/kg
prostate ED50 of 14.3 µg/kg, exhibiting 16-fold selectivity for
muscle over prostate (Table 2). This high level of anabolic drive
is comparable to the most potent known agents, although the
muscle selectivity observed is an order of magnitude lower than
previously seen with hydantoin 1.11 Compound 6c was shown
to be selective for androgen receptor and had no significant
activity in the related steroidal nuclear hormone receptors ER,
PR, GR, and MR.
An X-ray cocrystal structure of compound 6c with AR
(Figure 2A) and compound 1 from its complex with AR11
can be superimposed (protein only) and compared (Figure
2B) to reveal key differences. The combined binding interac-
tions of a nonclassical H-bond with R752 and the π-edge-face
interaction with F764 of the AR between the nitrile and aryl
rings of 6c, respectively, appear to be the predominating

N-Aryl-oxazolidin-2-imine Muscle SelectiVe AR Modulators
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2797
mL) was added, and the product was extracted with EtOAc (3 ×
5 mL). The combined organic layers were washed with saturated
aqueous NaHCO3 and brine, dried over MgSO4, and then filtered
and concentrated. Purification via flash chromatography provided
6a-g.
As a result of characterization of side products obtained
during the synthesis of SARM analogues, modifications to
the vectorial orientation of key pharmacophoric elements in
an earlier series were achieved and confirmed through anal-
ysis of X-ray cocrystal structures of a prototype ligand bound
to the AR. Relative to those more linearly oriented com-
pounds previously disclosed from these laboratories, the
modified ligand shape appears to correlate with enhanced in
vitro potency. This novel scaffold may provide an alternative
ligand design template for further drug discovery efforts to
identify improved SARMs for a range of indications.
Z-4-[(1R,7S,7aS)-7-Hydroxy-1-trifluoromethyl-tetrahydropyr-
rolo[1,2-c]oxazol-3-ylideneamino]-2-chloro-3-methylbenzonitrile (6c).
Compound 6c was prepared in two steps from 4c by following
the general cyclization method B (60% yield, sole product
isolated) and deprotection method D (93% yield). 1H NMR (500
MHz, CD3OD) δ 1.98 (dd, 1 H), 2.30 (dd, J ) 12.6, 5.5 Hz, 1
H), 3.49 (br s, 1 H), 3.61-3.77 (m, 1 H), 3.81 (dd, J ) 6.6, 3.8
Hz, 1 H), 4.19 (q, J ) 7.1 Hz, 1 H), 5.09 (dd, J ) 6.6, 3.8 Hz,
1 H), 5.48 (s, 0 H), 6.97 (d, J ) 8.2 Hz, 1 H), 7.47 (d, J ) 8.2
Hz, 1 H). 13C NMR (125 MHz, CD3OD) δ 15.3, 35.0, 48.5, 68.1,
74.6, 108.1, 117.9, 123.1, 124.4 (q, J ) 279), 132.3, 132.5,
137.6, 152.8; MS: m/z 360 [M + H]+. HRMS calcd for (M +
H) 360.0727, found 360.0724. HPLC 100% purity (Zorbax SB
C18 4.6 mm × 75 mm; 8 min gradient eluting with solvent A:
10% MeOH/90% water/0.2% H3PO4 and solvent B: 90% MeOH/
10% water/0.2% H3PO4; retention time ) 6.48 min); 99% purity
(Chiracel OD 4.6 mm × 250 mm; isocratic eluting with 20%
isopropanol in heptane; retention time ) 5.79 min). HRMS calcd
Experimental Section
General Chemistry Methods. Proton (1H) and carbon (13C)
NMR spectra were recorded on a JEOL 400 or 500 MHz, or on a
Bruker 400 MHz instrument. Analytical HPLC were performed on
a Shimadzu instrument using YMC C18 5 µm 4.6 mm × 50 mm
column with a 4 min gradient of 0-100% solvent A (90% MeOH/
90% H2O/0.2% H3PO4) and 100-0% of solvent B (10% MeOH/
90% H2O/0.2% H3PO4) with a 1 min hold. LC-MS spectra were
obtained on a Shimadzu HPLC and Micromass platform using
electrospray ionization. HRMS were obtained on a Micromass LCT
in lockspray with electrospray ionization. The preparative HPLC
was done on an automated Shimadzu system using the YMC ODS
C18 5 µm preparative columns with mixtures of solvent C (90%
MeOH/10% H2O/0.2% TFA) and solvent D (10% MeOH/90% H2O/
0.2% TFA) or mixtures of solvent E (90% CH3CN/10%H2O/0.2%
TFA) and solvent F (10% CH3CN/90% H2O/ 0.2% TFA). Other
reagents and solvents were obtained from commercial sources and
were used without further purification. All reactions were carried
out under a nitrogen atmosphere unless otherwise noted.
for (M
+ H) 360.0727, found 360.0724. Anal. calcd:
(C15H13ClF3N3O2) C, 50.08; H, 3.64; N, 11.68. Found: C, 49.97;
H, 3.37; N, 11.42. Stereochemistry was confirmed via X-ray
analysis, and this data can be found in the Supporting Informa-
tion for this article.
X-ray Crystallography. The AR LBD-6c complex was crystal-
lized at 20 °C by vapor diffusion in the hanging drop mode using
a 3 mg/mL concentration of 6c as previously described.15 Data to
1.95 Å resolution were collected at beamline ID32 at the APS
synchrotron and reduced with program HKL2000, and the structure
was refined with program BUSTER. The His-Tag and the first six
residues of the N-terminal and the last residue of the C-terminal
were not visible in the electron density and have been excluded
from the model. The final structure has an R-factor ) 20.1% (Rfree
) 23.8%) and contains 2229 atoms (2034 protein atoms, 24 ligand
atoms, and 171 solvent atoms).
Methods for Preparation of 6c: (2R,3S)-3-(tert-Butyldimethyl-
silanyloxy)-2-[(1R)-((2,2,2-trifluoro-1-hydroxyethyl)]-pyrrolidine-
1-carboxylic Acid (3-Chloro-4-cyano-2-methylphenyl)-amide (4c).
Compound 4c was prepared in 8% overall yield according to our
previously reported method.14 MS m/z 492 [M + H]+. H NMR
1
(400 MHz, CDCl3) δ 0.05 and 0.07 (br s, total 6 H), 0.84 (br s, 9
H), 1.94-2.21 (m, 2 H), 2.29 (br s, 3 H), 3.46-3.48 (m, 1 H),
3.52 (br. s., 1 H), 3.65 (br s, 1 H), 3.70-3.83 (m, 1 H), 4.11 (br s,
1 H), 4.42 (br s, 1 H), 5.21 (br s, 1 H), 7.49 (d, J ) 8.8 Hz, 1 H),
7.95 (d, J ) 8.8 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ -4.98,
14.54, 17.81, 25.60, 32.81, 44.56, 67.69, 72.28, 72.50, 116.66,
119.49, 126.50, 131.90, 136.95, 141.78, 156.67.
Acknowledgment. We thank the department of Pharma-
ceutical Candidate Optimization for bioanalytical and physico-
chemical profiling support.
Supporting Information Available: Preparation of and char-
acterization data for intermediates and final compounds 6a, 6b, 6d,
6e, 6f, 6g, 11, 12, 13, and 15 and single crystal X-ray structural
data for compound 6c. This material is available free of charge via
the Internet at http://pubs.acs.org.
Typical Procedures for Cyclizations to Compounds 6a-g.
Method A: To a solution of hydroxy urea 4 (0.140 mmol, 1.00
equiv) in THF (3 mL) at 0 °C was added a 1 M solution of t-BuOK
in THF (0.230 mmol, 1.60 equiv) and p-TsCl (0.470 mmol, 3.30
equiv). The mixture was stirred at 0 °C for 30 min and was diluted
with EtOAc. The layers were separated, and the organic layer was
washed with saturated aqueous NaHCO3 and brine and then dried
over MgSO4, filtered, and concentrated. Purification via flash
chromatography provided a mixture of silyl-protected 5 (major)
and silyl-protected 6 (minor) products. Method B: To a solution of
hydroxy urea 4 (0.250 mmol) in CH3CN (2 mL) at 0 °C was added
Ph3P (1.0 mmol, 4.0 equiv), CCl4 (2.0 mmol, 8.0 equiv), and NEt3
(1.0 mmol, 4.0 equiv), and the mixture was stirred at rt overnight.
The reaction was diluted with CH2Cl2 (ca. 20 mL) and then washed
with brine, dried over MgSO4, filtered, and concentrated. Purifica-
tion via flash chromatography provided the silyl-protected 6 as the
major products. The silyl groups were removed by one of the two
following methods. Method C: To a solution of silyl protected 6
(0.025 mmol, 1 equiv) in THF (1 mL) at 0 °C was added a 1.0 M
TBAF solution in THF (0.250 mmol, 10 equiv). After stirring at rt
for 1 h, saturated aqueous NH4Cl and EtOAc were added. The layers
were separated, and the organic layer was washed with brine and
then dried over MgSO4, filtered, and concentrated. Method D: To
a solution of silyl-protected 6 (0.055 mmol) in THF (2 mL) at 0
°C was added HF/pyridine mixture (∼2.3:1, 0.120 mL), and the
reaction was stirred at rt overnight. Saturated aqueous NaHCO3 (5
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