Metabolism-guided design of short-acting calcium-sensing receptor antagonists

Article abstract of DOI:10.1021/ml100058w

As part of a strategy to deliver short-acting calcium-sensing receptor (CaSR) antagonists, the metabolically labile thiomethyl functionality was incorporated into the zwitterionic amino alcohol derivative 3 with the hope of increasing human clearance through oxidative metabolism, while delivering a pharmacologically inactive sulfoxide metabolite. The effort led to the identification of thioanisoles 22 and 23 as potent and orally active CaSR antagonists with a rapid onset of action and short pharmacokinetic half-lives, which led to a rapid and transient stimulation of parathyroid hormone in a dose-dependent fashion following oral administration to rats. On the basis of the balance between target pharmacology, safety, and human disposition profiles, 22 and 23 were advanced as clinical candidates for the treatment of osteoporosis.

Full text of DOI:10.1021/ml100058w

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Metabolism-Guided Design of Short-Acting
Calcium-Sensing Receptor Antagonists
James A. Southers, Jonathan N. Bauman, David A. Price, Paul S. Humphries, Gayatri Balan,
John F. Sagal, Tristan S. Maurer, Yan Zhang, Robert Oliver, Michael Herr, David R. Healy, Mei Li,
Brendon Kapinos, Gwendolyn D. Fate, Keith A. Riccardi, Vishwas M. Paralkar,
Thomas A. Brown, and Amit S. Kalgutkar*
Pfizer Global Research and Development, Groton, Connecticut 06340
ABSTRACT As part of a strategy to deliver short-acting calcium-sensing receptor
(CaSR) antagonists, the metabolically labile thiomethyl functionality was incorpo-
rated into the zwitterionic amino alcohol derivative 3 with the hope of increasing
human clearance through oxidative metabolism, while delivering a pharmacolo-
gically inactive sulfoxide metabolite. The effort led to the identification of thioa-
nisoles 22 and 23 as potent and orally active CaSR antagonists with a rapid onset of
action and short pharmacokinetic half-lives, which led to a rapid and transient
stimulation of parathyroid hormone in a dose-dependent fashion following oral
administration to rats. On the basis of the balance between target pharmacology,
safety, and human disposition profiles, 22 and 23 were advanced as clinical
candidates for the treatment of osteoporosis.
KEYWORDS Calcium, CaSR antagonists, PTH, cytochrome P450, metabolite,
oxidation
steoporosis affects a substantial proportion of the
elderly population and causes notable morbidity,
deterioration in quality of life, and mortality due to
transient for bone anabolism since sustained activation
causes prolonged PTH secretion and a catabolic state, such
as hyperthyroidism.4,5 To achieve such a PD effect, a CaSR
antagonist must demonstrate rapid oral absorption and a
short pharmacokinetic (PK) half-life (t1/2) of ∼1 h [ideally
achieved through a human blood clearance (CLb) and steady
state distribution volume (Vdss) of 10 mL/min/kg and 1 L/kg,
respectively].6
A number of CaSR antagonists have been reported in the
literature.6-9 Results of phase 2A clinical trials have also
been reported with ronacaleret (Figure 1) and JTT-305.10,11
Despite a positive proof-of-concept in a 28 day study in
postmenopausal women, a dose-ranging clinical trial of
ronacaleret was discontinued due to poor effects on
BMD.10 While the reason(s) for lack of efficacy of ronacaleret
remains unclear, confidence in the mechanism was restored
shortly after the disclosure that JTT-305 significantly in-
creased lumbar spine BMD in a 12 week clinical trial while
showing favorable effects on markers of bone formation and
resorption in patients with postmenopausal osteoporosis.11
As such, the structure of JTT-305 is unknown but is believed
to be in similar chemotype to that of ronacaleret.
O
associated fragility fractures.1 Agents for the treatment of
osteoporosis are classified as either antiresorptive or ana-
bolic. While antiresorptive agents (e.g., bisphosphonates
and estrogen) prevent further bone loss, they cause rela-
tively small increases in bone formation. In contrast, ana-
bolic agents act by stimulating osteoblast function and new
bone formation. The only anabolic agent currently available
in the United States is teriparatide (Forteo), a synthetic 1-34
amino acid peptide fragment of the human parathyroid
hormone (PTH), which has been shown to increase bone
mineral density (BMD) and reduce fracture rates in osteo-
porosis patients after daily subcutaneous administration.2
Aviable alternative to an injectible agent is the identification
of a small molecule agent that would stimulate secretion of
endogenously stored PTH from the parathyroid glands. PTH
secretion is tightly regulated by the G-protein-coupled cal-
cium-sensing receptor (CaSR) expressed on the surface of
the parathyroid cells.3,4 CaSR modulates circulating levels
of calcium; a hypocalcemic state (low serum calcium con-
centrations) results in PTH release from the parathyroid
glands, whereas increase in calcium suppresses the release
of this hormone.3,4 Small molecule CaSR antagonists repli-
cate a hypocalcemic state and stimulate PTH release.4,5
Pharmacodynamic (PD) studies with prototype CaSRantagonists
such as NPS-2143 (Figure 1) reveal that the profile of PTH
stimulation following CaSR antagonism must be rapid and
Toward the pursuit of proprietary chemotypes, our labora-
tory recently disclosed a series of tricyclic zwitterionic amino
Received Date: April 8, 2010
Accepted Date: May 10, 2010
Published on Web Date: May 13, 2010
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furnished 18 and 19, which were characterized as the corre-
sponding hydrochloride salts. Lewis acid-mediated epoxide ring
opening in 10 by 18 and/or 19 afforded 20 and 21, respectively,
which were hydrolyzed to title compounds 22 and 23, respec-
tively (Scheme 1C). Putative sulfoxide metabolites 24 and 26
were synthesized from the oxidation of 22 and 23 in the
presence of N-bromosuccinimide. Oxidation of 22 and 23 in
the presence of Oxone afforded corresponding sulfone 25 and
27 metabolites, respectively.
In vitro CaSR antagonist potency was examined using a
fluorimetric imaging plate reader (FLIPR)-based assay, which
measures the ability of test compounds to block increases in the
concentration of cytoplasmic calcium in HEK293 cells expres-
sing human CaSR. Ronacaleret and 3, which were included as
positive controls, revealed CaSR antagonist potency (IC50)
values of 0.11 and 0.016 μM, respectively. Compounds 22
and 23 were superior CaSR antagonists with IC50 values of
0.009 and 0.005 μM, respectively. Selectivity against R2β and
β2-adrenergic receptor binding, human ether-a-go-go related
gene (hERG), and CYP2D6 inhibition was also examined, given
the association of such off-target pharmacologies with some
amino alcohol-based CaSR antagonists.9 In binding assays
(Table 1 ), weak cross-reactivity with the R2β and β2 receptors
and hERG ion current was noted with ronacaleret, 3, 22, and
23. Competitive CYP2D6 inhibition was also observed with 3,
22, and 23 (IC50=1.3-3.7 μM). In contrast, ronacaleret did not
inhibit CYP2D6 activity (IC50>30 μM). Because basic amino
alcohols have been reported as inhibitors of several mono-
amine transporters,9 ronacaleret, 3, 22, and 23 were tested for
inhibition of SER, norepinepherine (NER), and dopamine (DA)
transporters. Inhibitory effects against SERT (IC50=12->25
μM), NERT(IC50=9.0->25 μM), andDAT(IC50=4.0-4.5 μM)
by 3, 22, and 23 were generally weak in nature (Table 1). In
contrast, ronacaleret appeared to possess significantly more
potent interactions against SERTand DAT.
Pleased with the results of the in vitro pharmacologic
evaluation and in particular with the>1000-fold selectivity
over hERG, we focused our attention on the metabolism
of 22 and 23 in HLM. The biotransformation pathways
of 22 (MHþ=508, panel A) and 23 (MHþ=526, panel B) in
NADPH-supplemented HLM were similar and consisted pri-
marily of the sulfoxide metabolites 24 (MHþ=524) and 26
(MHþ =542), respectively (Figure 2). Further oxidation to
the corresponding sulfones 25 (MHþ=540) and 27 (MHþ=
558) was also detected as a minor metabolite fate. The meta-
bolites were identified unambiguously via comparison of
retention times and mass spectra with those of the authen-
tic standards. For the success of our overall strategy, we
knew that any (circulating) metabolite formed must be
significantly less active than the parent to avoid sustained
PTH stimulation. To our delight, both the sulfoxide and the
sulfone metabolites of 22 and 23 were devoid of CaSR
antagonism (IC50 values >100 μM). The potentially toxic
mercaptan metabolite derived from thioanisole S-demethy-
lation in 22 and 23 was not detected in HLM incubations.
Finally, inclusion of CYP3A4 inhibitor ketoconazole in HLM
incubations eliminated metabolite formation in 22 and 23,
implying that CYP3A4 was responsible for their biotransfor-
mation.
Figure 1. Structures of representative CaSR antagonists.
alcohol (e.g., 1 and 2)-based CaSR antagonists (Figure 1).8
While members within the series displayed requisite CaSR
pharmacology, the projected low CLb using human liver
microsomes (HLM) for leads 1 and 2 was concerning.
Consequently, we directed our attention to the optimization
of the amino alcohol chemical space in search of compounds
endowed with not only analogous pharmacologic properties
but also improvements in human PK profiles. Comparison
of the HLM stability of NPS-2143 with zwitterionic amino
alcohols suggests that the carboxylic acid moiety signifi-
cantly reduces lipophilicity, resulting in reduced affinity
toward metabolism by cytochrome P450 (CYP) enzymes.8
Metabolic profiling of several zwitterionic amino alcohols
in HLM revealed trace amounts of hydroxylation on the
2-methylpropan-2-amine substituent (e.g., indanyl group in
1 and ronacaleret and 2-fluorotolyl motif in 2 and 312) to
be a common and dominant metabolic fate. We reasoned
that strategic placement of a metabolically labile functional
group on the region predisposed to CYP metabolism would
provide the necessary boost in metabolic clearance. For this
assessment, we decided to focus our efforts on biaryl
carboxylic acids (e.g., compound 3, Figure 1) described in
a patent application by Japan Tobacco.12 From prior in-
house experience in the selective serotonin (SER) reuptake
inhibitor program,13 we were aware that CYP-catalyzed
thioalkyl S-oxidation can be an efficient and rapid metabolic
process and therefore offered an attractive avenue of pursuit
in the present situation. Herein, we describe our efforts to
optimize the human disposition profile of 3 while maintain-
ing primary CaSR pharmacology and selectivity, which
resulted in the identification of clinical candidates 22 and 23.
The synthesis of the common epoxide intermediate 10 is
shown in Scheme 1A. Stereoselective reduction of 2-bromo-
acetophenone (4) with (þ)-diisopinocampheyl chloroborane
[(þ)-DIP-Cl] generated the (R)-form of secondary alcohol 5
(>98% ee),16 which was reacted with glycidyl tosylate to afford
bromo epoxide 6 in a 10:1 ratio of diastereomers. Palladium-
catalyzed coupling of 6 with the pincacol boronate ester 8
afforded 10 as a viscous oil. Amines 18 and 19 were synthesized
from the corresponding bromothioanisole derivatives 12 and
13, respectively (Scheme 1B). Grignard formation in 12 and 13
followed by reaction with 3-chloro-2-methylpropene yielded
olefins 14 and 15, which were converted to chloroacetamide
analogues 16 and 17, respectively, via a Ritter reaction. Depro-
tection of 16 and/or 17 with thiourea in the presence of AcOH
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Scheme 1. Synthesis of Compounds 22 and 23a
a Conditions: (a) (þ)-DIP-chloride, THF, -25 °C, diethanolamine. (b) Toluene-4-sulfonic acid (R)-1-oxiranylmethyl ester, NaH, THF, DMF, 0 °C to room
temperature. (c) MeOH, H2SO4, reflux, 20 h. (d) Bis(Pinacolato)diboron, [1,10-bis(diphenylphosphino)ferrocene] dichloropalladium(II), KOAc, 80 °C
and 3 h to room temperature and 16 h. (e) [1,10-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), Na2CO3, EtOH, reflux 3 h. (f) Br2, CH2Cl2,
0 °C to room temperature. (g) Mg, cat. I2, CuI, 3-chloro-2-methylpropene 0 °C to room temperature, aqueous NH4Cl. (h) Chloroacetonitrile, AcOH,
H2SO4, 0 °C to room temperature. (i) AcOH, EtOH, 100 °C, 16 h. (j) Compound 18 or 19, 1.1 equiv LiClO4, toluene, 50 °C. (k) LiOH, MeOH, H2O, 50 °C,
16 h. (l) N-Bromosuccinimide, silica gel, CH2Cl2, room temperature. (m) Oxone, MeOH-H2O, 0 °C to room temperature.
Table 1. CaSR Potency and Selectivity Data
IC50 (μM)a
CaSR FLIPR R2β binding β2 binding Nav1.5 binding hERG binding CYP2D6 SERT binding NER binding DA binding
compd
ronacaleret
0.11
9.0
2.2
8.2
6.0
>30
6.8
>30
>30
>30
>30
23
19
14
>30
2.5
0.19
>25
3.6
>25
18
9.0
1.4
4.0
4.4
4.5
3
0.016
0.009
0.005
22
23
10
10
3.7
1.3
14
12
7.0
a IC50 values are means of at least three independent experiments. CaSR IC50 values represent the average of 15-20 separate determinations.
Our next objective was human CLb predictions for 22 and
23. In NADPH-supplemented HLM, 22 and 23 rapidly de-
graded with t1/2 values of less than 10 min. Scale-up of the
microsomal t1/2 data using the well-stirred model14 provided
a complementary range of predicted human CLb values for
22 (6.0 mL/min/kg) and 23 (9.0 mL/min/kg) (Table 2).
Ronacaleret and 3 were relatively more stable toward
metabolism in HLM (t1/2 = 50-60 min) yielding CLb values
of ∼1.0 mL/min/kg. In vitro-in vivo correlation (IVIVC)
studies were undertaken in the rat to increase confidence
in human CLb projections (Table 2). Following intravenous
(iv) administration, in vivo CLb values of ronacaleret, 3, 22,
and 23 were 2.0-4.0-fold greater than the corresponding
CLb estimates from rat liver microsomes. While the higher
CLb values of 22 and 23 relative to 3 clearly reflect the
success of our design strategy involving the implementation
of the thioalkyl group to boost metabolism, lack of a robust
rat IVIVC caused some concern in relation to the confidence
in human CLb projections. Although urinary excretion of
unchanged parent was insignificant (<1% of the dose), the
detection of acyl glucuronide conjugates (22-acyl glucuro-
nide, MHþ = 684; 23-acyl glucuronide, MHþ = 702) in rat
urine indicated glucuronidation as an additional route of
elimination, which may explain the weak IVIVIC in the rat.
The likelihood that HLM CLb values will underpredict in vivo
CLb of 22 and 23 in humans is high since in vitro metabolism
studies in human hepatocytes also demonstrated the pre-
sence of the acyl glucuronide metabolites of 22 and 23,
in addition to the S-oxidation products detected in HLM
incubations. The inability of in vitro systems to accurately
predict glucuronidation-mediated clearance confounds our
HLM CLb predictions to a certain degree, and ultimate
resolution of the issue will occur in the first in-human PK
study. It is of interest to note that despite the high rat
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clearances noted with 22 and 23, the compounds were
sufficiently exposed after oral (po) administration as suspen-
sions in methyl cellulose (F=25-28% at the 10 mg/kg dose;
see Table 2).
transient and returned to levels that were not significantly
higher than baseline within 60-120 min postdose.
In summary, we have improved upon the CaSR pharma-
cology and human PK profile of the lead chemical matter
(e.g., compounds 1-3) with 22 and 23, respectively. Several
attractive features of 22 and 23 also emerged in the course of
detailed profiling of their disposition characteristics. For
instance, lack of competitive or time-dependent inhibition
of CYP3A4 activity in HLM (IC50 > 30 μM) by 22 and 23 indi-
cates a low risk of nonlinear PK and/or PK interactions with
CYP3A4 substrates. Drug-drug interactions via CYP2D6
inhibition by 22 and 23 are also deemed unlikely, given
the low predicted human plasma concentrations (unbound
Cmax ∼ 25-34 nM) at efficacious doses. Furthermore, weak
inhibitory effects on the organic anion transporting poly-
peptide 1B1 by 22 (IC50 = 13 μM) and 23 (IC50 = 40 μM)
Endogenous PTH stimulatory effects were evaluated in
rats following iv and po administration. Administration of a
single iv dose (1 mg/kg) of 22 or 23 resulted in rapid
stimulation (within 2 min postdose) of plasma PTH with
peak concentrations of 1106 and 979 pg/mL, respectively,
which were approximately 8-10-fold higher than basal
levels of the hormone in vehicle-treated animals. Oral ad-
ministration of 22 and 23 at doses of 1, 3, 10, 30, and 100 mg/kg
(suspensions in 0.5% methyl cellulose) produced high levels
of PTH secretion in a dose-dependent manner. A represen-
tative PK/PD effect plot for 22 is depicted in Figure 3. Plasma
PTH reached tmax at 15 min postadministration for all dose
groups; associated free Cmax values for 22 and 23 at these
doses ranged from 0.3 to 89 nM. The free Cmax values of 14
and 9.7 nM for 22 and 23, respectively, at the 10 mg/kg dose
that provided a robust PTH response provided adequate
coverage of the in vitro CaSR IC50. Consistent with the short
effective t1/2 values of 22 and 23, plasma PTH elevation was
Figure 2. Extracted ion chromatogram of NADPH-supplemented
HLM incubations of 22 (A) and 23 (B).
Figure 3. Mean PK/PD profile of 22 following po dosing in the
Sprague-Dawley rat (n = 4/dose).
Table 2. Rat PK Data for CaSR Antagonists Ronacaleret, 3, 22, and 23a
compd
dose (mg/kg)
route
RLM CLb
13
C
max (ng/mL)
t
max (h)
CLb (mL/min/kg)d
Vdss (L/kg)
t
1/2 (h)e
F (%)
ronacaleret
1
10
iv
62
6.0
2.0
pob
136
0.4
12
50
25
28
3
1
10
iv
8.7
30
25
75
85
0.6
2.1
1.1
2.1
poc
1980 ( 381
273 ( 71
0.7 ( 0.3
0.5 ( 0.0
0.5 ( 0.0
22
23
1
10
iv
0.44
0.41
poc
1
10
iv
20
poc
638 ( 99.6
a PK studies were conducted in male Sprague-Dawley rats (n = 2-5). Compounds were administered in glycerol formal containing 2% DMSO (iv)
or as suspensions in 0.5% methyl cellulose (po). b Administered as the hydrochloride salt (n = 2). c Administered in free base form. d CLb values were
obtained from plasma clearance divided by the blood partitioning ratio. e Half-life values represent the terminal elimination (β) phase.
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mitigate the likelihood of PK interactions with statins,
many of which are substrates for hepatic uptake by this
transporter.15 Furthermore, with the involvement of multi-
ple elimination mechanisms (e.g., CYP3A4 oxidation and
glucuronidation) for 22 and 23, the fraction of drug meta-
bolized via a single clearance pathway is reduced and so is
the potential for PK interactions involving that pathway.
From a drug safety perspective, no clinical signs or histological
changes were noted with 22 and 23 in subchronic toxicity
testing in rats and dogs at oral doses of 5, 50, and 500 mg/kg.
Furthermore, 22 and 23 were devoid of mutagenic re-
sponses in the Salmonella Ames assay. The necessity for
additional safety testing of metabolites17 is deemed unlikely
since no human specific metabolites were detected in in
vitro metabolism studies. On the basis of in vitro potency, in
vivo oral efficacy, safety, and favorable human disposition
attributes, compounds 22 and 23 were selected as clinical
candidates for the treatment of osteoporosis.
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SUPPORTING INFORMATION AVAILABLE Experimental
details for the synthesis and characterization of CaSR antagonists 22
and 23 and their primary metabolites, respectively; protocols for in
vitro and in vivo pharmacology and disposition studies; and represen-
tative LC-MS/MS spectral data from metabolism studies. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) Deal, C. Potential New Drug Targets for Osteoporosis. Nature
Clin. Pract. Rheumatol. 2009, 5 (1), 20–27.
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T. Randomized, Single-Blinded Placebo-Controlled Study of a
Novel Calcilytic, JTT-305, in Patients with Postmenopausal
Osteoporosis. ASBMR Abstract 1131.
(12) Shinagawa, Y.; Inoue, T.; Kiguchi, T.; Ikenogami, T.; Ogawa,
N.; Fukuda, K.; Nakagawa, T.; Shindo, M.; Soejima, Y. Pre-
paration of Arylcarboxylic Acid Derivatives as CaSR Antago-
nists. WO 2004/094362.
(13) Middleton, D. S.; Andrews, M.;Glossop, P.;Gymer, G.; Hepworth,
D.; Jessiman, A.; Johnson, P. S.; MacKenny, M.; Stobie, A.; Tang,
K.; Morgan, P.; Jones, B. Designing Rapid Onset Selective
Serotonin Re-uptake Inhibitors. Part 3: Site-Directed Metabolism
as a Strategy To Avoid Active Circulating Metabolites: Structure-
Activity Relationships of (Thioalkyl)phenoxy Benzyl Amines.
Bioorg. Med. Chem. Lett. 2008, 18 (19), 5303–5306.
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Drugs from Hepatic Microsomal Intrinsic Clearance Data: An
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AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: 860-715-2433. Fax: 860-441-1128. E-mail: amit.
kalgutkar@pfizer.com.
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