Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639

Article abstract of DOI:10.1021/acsmedchemlett.5b00023

The discovery of a novel peripherally acting and selective Ca_v3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bi

Full text of DOI:10.1021/acsmedchemlett.5b00023

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Letter
Optimization of ADME Properties for Sulfonamides Leading to
the Discovery of a T-Type Calcium Channel Blocker ABT-639
Qingwei Zhang, Zhiren Xia, Shailen Joshi, Victoria E Scott, and Michael F Jarvis
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.5b00023 • Publication Date (Web): 28 Apr 2015
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ACS Medicinal Chemistry Letters
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Optimization of ADME Properties for Sulfonamides Leading to the
Discovery of a T-Type Calcium Channel Blocker ABT-639
Qingwei Zhang,* Zhiren Xia, Shailen Joshi, Victoria E. Scott and Michael F. Jarvis
Neuroscience Research, AbbVie, 1 North Waukegan Rd., North Chicago, IL, 60064 USA
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KEYWARDS: Cav3.2, T-type calcium channel, pain, Sulfonamides, ADME
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ABSTRACT: The discovery of a novel peripherally acting and selective Cav3.2 Tꢀtype calcium channel blocker, ABTꢀ639 is
described. HTS hits 1 and 2 which have poor metabolic stability were optimized to obtain 4, which has improved stability and oral
bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABTꢀ639. Following oral
administration, ABTꢀ639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly
alter psychomotor or hemodynamic function in the rat.
Voltageꢀgated calcium channels (VGCC) play an important
role in the regulation of calcium influx into cells in response to
change membrane conductance, thereby activating various
H
N
N
N
N
N
S
S
physiological functions, such as neurotransmitter release,
cellular excitability, muscle contraction and many others.1
These channels can be classified into lowꢀvoltage activated Tꢀ
type and highꢀvoltage activated Lꢀtype and P/Qꢀ, Nꢀ and Rꢀ
types calcium channels. Nꢀtype calcium channels are found
primarily at presynaptic terminals and are involved in
neurotransmitter release.2,3 Tꢀtype channels are primarily
involved in postsynaptic excitability.4 Recent studies have
shown that Tꢀtype calcium channels may be important
therapeutic targets for the treatment of several
neurophysiological disorders, including as epilepsy,5 pain,6,7,8
hypertension,9 sleep architecture,10 tremor,11 and Parkinson’s
disease.12, 13
O
O
O
O
O
O
O
2
1
N
H
O
F
O
N
O
S
S
N
H
N
H
O
O
O
F
3
4
Figure 1. Structures of hits 1, 2, and lead 3, 4
Since the potency of 1 and 2 were in a similar range to other
previously described T/Nꢀtype calcium channel blockers, lead
optimization efforts were focused on improving ADME
properties for these hits.20 Modification of both sulfonamide
and amide sides of these hits led to identification of a new lead
3, which has a lower cLogP than 1 and 2. Compound 3
afforded 29% oral bioavailability in rats. Unfortunately, the
halfꢀlife (t1/2) of 3 following i.v. dosing at 5 ꢀmol/kg was only
0.31 hr, mainly due to the high plasma clearance rate (CLp) of
1.66 L/hr/kg and a low volume distribution (Vβ) of 0.75 L/kg
(Table 1).
Cav3.2 is the predominant Tꢀtype calcium channel isoform in
sensory nerves that modulate nociception, and is expressed in
dorsal root ganglion (DRG) neurons, peripheral receptive
fields, spinal cord dorsal horn and brain.14 Bourinet et al
demonstrated that silencing of Cav3.2 channel strongly
reduced acute and neuropathic nociception.15 Intrathecal
administration or local injection of Cav3.2ꢀspecific, but not
Cav3.1 and Cav3.3ꢀspecific antisense oligonucleotides
produces a significant knockdown of Cav3.2 Tꢀtype currents in
nociceptive DRG neurons, and robust longꢀlasting and
reversible mechanical and thermal antinociceptive effects.
Jagodic et al. demonstrated that following chronic constriction
injury (CCI) of the sciatic nerve induced upregulation of Tꢀ
type calcium channel currents in small rat DRG.16
Modulation of the Cav3.2 (α1H) channel controls the
sensitization of nociceptors, the peripheral painꢀsensing
neurons.17 These results further support Cav3.2 Tꢀtype
Table 1. RLM and PK Parameters of Compounds 1, 2, 3
and 4
RLM a
(%)
cLogP
CLp
t1/2
(hr)
F (%)
(p.o.)
Vβ
(L/hr/kg)
(L/kg)
0.3
0.1
46
4.4
5.3
3.1
2.8
4.94
11.1
0.75
0.65
1.90
3.47
1.66
1.79
1.80
2.16
0.31
0.25
0.5 b
1.9 b
1
2
3
4
channels as
sensitivity.
a mechanism for modulating nociceptive
29.0 c
31.3 c
68
High throughput screening (HTS) generated a number of
sulfonamides hits including 1 (IC50 = 3 ꢀM) and 2 (IC50 = 5
ꢀM) (Figure 1) against Cav3.2 Tꢀtype channel in a FLIPR
based Ca2+ flux assay.18,19 However, HTS hits 1 and 2 are
metabolically unstable in rats and both have very poor oral
bioavailability (F = 0.5% and 1.9%, respectively) (Table 1).
aRat Liver Microsomal stability. Percentage remaining after 30
min at 1ꢀM. b3 µM/kg iv and po. c5 µM/kg iv and 30 µM/kg po.
Oral formulation: PEG400: Cremophor EL: Oleic Acid (10:10:80,
by weight 2 ml/kg).
After evaluating several diamines, a rigid bicyclic diamine
was identified to replace dimethylmorpholine in 3. Compound
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4 demonstrated better stability in rat liver microsomes Substituent on aromatic ring can influence the microsomal
stability and pharmacokinetic properties of the compounds .21
Introduction of the F or Cl atom to the central aromatic ring of
4 led to the discovery of ABTꢀ639 (Figure 2), which has a
significantly decreased plasma clearance rate of 0.55 L/hr/kg.
The volume distribution (Vβ) was increased to 2.7 L/kg, and
the halfꢀlife (t1/2) of ABTꢀ639 was improved to 3.3 hr in rats.
The oral bioavailability in rats was also significant improved
(F = 73%). The increase in volume distribution in rat and
monkey may be due to the increase of tissueꢀbinding or
partitioning into fat since the cLogP (3.8) of ABTꢀ639 is
larger than the cLogP (1.79) of 4.22 Compound 10 with
dichloroꢀsubstitutes on the central aromatic ring was prepared
and showed weaker potency (IC50 = 19 ꢀM) against Cav3.2 Tꢀ
type calcium channel with 44% oral bioavailability. Addition
of a methyl group to the sulfonamide side of ABTꢀ639 gives
compound 11 (Figure 2). Remarkably, compound 11 had
decreased stability in rat (RLM) and human liver microsomes
(HLM) from 81 ꢀ 95% to less than 0.01%. The (S)ꢀenantiomer
of ABTꢀ639 was also synthesized, it has 57% oral
bioavailability in rats.
1
2
3
4
5
6
7
8
compared to 1, 2 and 3. However, the plasma clearance rate
of 4 is still high (1.79 L/hr/kg) with a volume distribution (Vβ)
of 0.65 L/kg in rats. In order to further improve the ADME
properties and PK profile of 4, compounds 5 to 9 and the (S)ꢀ
enantiomers 4b to 6b with different R2 groups which have
electronꢀwithdrawing substituents on anilines were
investigated to compare their plasma clearance (CLp) and oral
bioavailability (Table 2).
We observed that the plasma
clearance (CLp) rate of the (R)ꢀenantiomers (4, 5, and 6) is
lower than the (S)ꢀenantiomers (4b, 5b and 6b), and the oral
bioavailability in rats is improved for the (R)ꢀenantiomers. i.e.
compound 4b, the (S)ꢀenantiomer of 4 shows higher plasma
clearance (3.36 L/hr/kg) than (R)ꢀenantiomer 4. Compound 7
with 2ꢀchloroaniline had increased CLp, and decreased
bioavailability compared to 4, but compounds 5, 8, 6 and 9
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with
2,3ꢀ,
2,6ꢀdifluoroaniline,
4ꢀ
and
2ꢀ
(trifluoromethyl)aniline had lower CLp and higher
bioavailability. Compounds 6 and 6b have an excellent PK
profile with CLp of 0.45 ꢀ 0.81 L/hr/kg and oral bioavailability
of 76 ꢀ 100%. However, compound 4 is the only one in the
Table 2 which shows IC50 = 10.6 ꢀM potency, other
compounds in Table 2 are weak Cav3.2 Tꢀtype calcium
channel blockers (<30% inhibition @10 ꢀM). Our next
attempt was to add the halogen atoms to the central aromatic
ring since it is possible that the high plasma clearance rate was
also due to the metabolic oxidation of the central aromatic
ring.
•HCl
N
Cl
F
N
O
S
H
N
H
O
O
F
ABT-639
RLM = 81%, HLM = 95%
F = 73%, t1/2 = 3.3 hr
Cl
Cl
Cl
F
Table 2.a Pharmacokinetic Parameters of Compounds 4 to
9 and 4b to 6b
N
H
N
H
N
O
N
O
N
S
S
N
H
O
O
O
O
F
F
10
F = 44%; t1/2 = 2.99 hr
11
R1
O
R2
S
RLM = 0.04%, HLM < 0.01%
O
O
___________________________________________________________________________________
Figure 2. ABTꢀ639 and its analogs 10 and 11
Plasma clearance
CLp (L/hr/kg)
bioavailability (p.o.)
F (%)
R1
R2
Compound
___________________________________________________________________________________
Scheme 1. Synthesis of ABTꢀ639 and Compounds 4 ꢀ11a
N
1.79
4
31
N
R1
R2
N
R1
R2
H
H
F
a
___________________________________________________________________________________
Cl
O
HO
O
S
N
S
Cl
3.36
28
Cl
O
O
N
4b
O
O
N
H
H
b
F
___________________________________________________________________________________
N
1.21
44
5
R1
R2
N
R1
O
R2
R6
N
F
N
H
N
H
c
R5
R4
H
H
F
N
O
N
O
___________________________________________________________________________________
S
S
Cl
N
H
N
O
O
O
2.28
29
R3
5b
N
N
F
H
4, R1 = R2 = R4 = R5 = R6 = H, R3 = F
5, R1 = R2 = R5 = R6 = H, R3 = R4 = F
H
F
___________________________________________________________________________________
d
6, R1 = R2 = R3 = R4 = R6 = H, R5 = CF3
7, R1 = R2 = R4 = R5 = R6 = H, R3 = Cl
8, R1 = R2 = R4 = R5 =H, R3 = R6 = F
9, R1 = R2 = R4 = R5 = R6 = H, R3 = CF3
10, R1 = R2 = Cl, R4 = R5 = R6 = H, R3 = F
CF3
N
0.45
100
6
N
Cl
F
N
N
H
H
H
___________________________________________________________________________________
N
O
CF3
S
N
N
6b
0.81
76
O
O
N
ABT-639, R1 = Cl, R2 = R3 = F, R4 = R5 = R6 = H
F
N
11
H
H
___________________________________________________________________________________
aReagents and conditions: (a) oxalyl chloride, CH2Cl2, RT,
overnight; (b) (R)ꢀoctahydropyrrolo[1,2ꢀa]pyrazine, Na2CO3,
CH2Cl2, RT, 5ꢀ18 hrs; (c) 2ꢀfluoroaniline or other substitutedꢀ
anilines , RT, overnight. (d) 2ꢀfluoroꢀNꢀmethylaniline, RT,
overnight.
N
1.93
5.8
7
N
N
H
H
Cl
___________________________________________________________________________________
F
N
0.92
54
8
N
N
H
H
F
___________________________________________________________________________________
N
0.74
57
9
N
Synthesis of ABTꢀ639 and its analogs is outlined in Scheme
1. ABTꢀ639 was obtained in 77% overall yield in 3 steps with
one step purification from commercially available starting
N
H
H
CF3
___________________________________________________________________________________
a5 µM/kg iv and 30 µM/kg po. Oral formulation: PEG400:
Cremophor EL: Oleic Acid (10:10:80, by weight 2 ml/kg).
materials.
2ꢀchloroꢀ5ꢀ(chlorosulfonyl)ꢀ4ꢀfluorobenzoyl
chloride was prepared by reaction of 2ꢀchloroꢀ5ꢀ
(chlorosulfonyl)ꢀ4ꢀfluorobenzoic acid with oxalyl chloride at
room temperate in the presence of DMF as a catalyst.
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Addition of one equivalent of (R)ꢀoctahydropyrrolo[1,2ꢀ ABTꢀ639 doseꢀdependently attenuates nociception in a
1
2
3
4
5
6
7
8
a]pyrazine to this resulting benzoyl chloride slowly over 1 hr
generated the amide intermediate, (R)ꢀ4ꢀchloroꢀ2ꢀfluoroꢀ5ꢀ
(octahydropyrrolo[1,2ꢀa]pyrazineꢀ2ꢀcarbonyl)benzeneꢀ1ꢀ
sulfonyl chloride. Since the amide formation is at a much
faster rate than the sulfonamide formation, very little or no
capsaicinꢀinduced secondary mechanical hyperalgesia model
(CapꢀSMH) (Figure 3). The antinociceptive activity of ABTꢀ
639 in this model is consistent with its doseꢀdependent
antinociceptive activity in multiple models of neuropathic
23
pain.18,
Additionally, ABTꢀ639 did not produce any
side products were detected by LCꢀMS.
Subsequent
decrement in balance or motor performance in the rat Edge
(ED50 > 300 mg/kg or rat plasma 114 µg/ml, p.o.). In rat
cardiovascular (CV) studies, intravenous administration (i.v.)
of ABTꢀ639 yielded negligible changes from vehicle control
on mean arterial pressure (MAP), heart rate (HR), left
ventricular contractility (dP/dt50), and vascular resistance (VR)
at concentrations (30 mg/kg, plasma concentration of 43.9
ꢀg/ml).18
sulfonamide formation was completed overnight by addition
of 2ꢀfluoroaniline to afford ABTꢀ639 after purification by
chromatography. Compound 10 was prepared starting from
9
commercially
available
2,4ꢀdichloroꢀ5ꢀ
10
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(chlorosulfonyl)benzoic acid by following the same synthetic
route of preparation of ABTꢀ639. Compound 11 was obtained
in 71% overall yield by using the same procedures. 2ꢀfluoroꢀ
Nꢀmethylaniline was used at the last step (Scheme 1, step d).
Compounds 3 to 9 and 4b to 6b were synthesized in 50 ꢀ 89%
yield by a oneꢀpot reaction from the commercially available 3ꢀ
(chlorosulfonyl)benzoyl chloride by following the same
procedures (Scheme 1, steps b and c).
ABTꢀ639 is a selective voltageꢀdependent Cav3.2 Tꢀtype
calcium channel blocker. It blocks human Tꢀtype (Cav3.2)
channels with IC50 = 2.3 ꢀM, and also blocks low voltage
activated currents in native rat DRG neurons (IC50 = 7.6
ꢁM).17 ABTꢀ639 shows little or no activity at other calcium
channels (Lꢀtype, Nꢀtype, and P/Qꢀtype) and is inactive (IC50
> 10 µM) across a wide array of cell surface receptors and ion
channels.18
Table 3.
species
Pharmacokinetic profile of ABT-639 across
species
CLp
(L/hr/kg)
0.55
0.045
0.11
t1/2
F
Microsomal
Vβ
(L/kg)
2.7
0.3
1.35
(hr) (%)a Stability (%)
Figure 3. ABTꢀ639 dose dependently reduces tactile allodynia in
the rat CapꢀSMH model. ABTꢀ639 was administered 1 hr before
behavioral testing. Gabapentin (Gaba, 500 ꢀM/kg, i.p.) was
included as a positive control for assay sensitivity.
ratb
dogc
3.3
4.9
8.3
73
88
95
81
100
88
monkeyc
aOral formulation:
PEG400: Cremophor EL: Oleic Acid
(10:10:80, by weight 2 ml/kg). b5 µM/kg iv and 30 µM/kg po. c1
mg/kg iv and po.
We have described here the discovery of a novel selective Tꢀ
type calcium channel blocker, ABTꢀ639. Starting from HTS
hits 1 and 2 with poor metabolic stability, we replaced the 2ꢀ
methylindoline with aniline to improve the rat (RLM) and
human liver (HLM) microsomal stability. Subsequently, we
optimized the new lead 3 by incorporating a novel bicyclic
fused diamine. We then introduced the F and Cl atoms to the
central aromatic ring to improve the oral bioavailability,
metabolic stability, decrease the plasma clearance rate,
increase the halfꢀlife (t1/2), and led to discovery of a novel Tꢀ
type calcium channel blocker ABTꢀ639. ABTꢀ639 displayed
good selectivity against Nꢀtype, P/Qꢀtype, Lꢀtype calcium
channel and hERG channel. ABTꢀ639 has an excellent PK
profile with high oral bioavailability in all species. In vivo,
ABTꢀ639 doseꢀdependently reduces nociception in a chronic
pain model, with no significant cardiovascular effects at
analgesic doses.
The pharmacokinetic profile of ABTꢀ639 was evaluated in
rat, dog and monkey, respectively. The data are shown in
Table 3. ABTꢀ639 exhibits moderate to low plasma clearance
(CLp) ranging from 0.55 L/hr/kg in rat to 0.045 L/hr/kg in
dog. It also demonstrates moderate to lowꢀmoderate volume
distribution values in these three animal species. The halfꢀlife
(3.3, 4.9 and 8.3 hrs) and high oral bioavailability (73, 88 and
95%) in rat, dog and monkey are in agreement with the liver
microsomal stability data (81ꢀ100% remaining after 30 min).
ABTꢀ639 shows good aqueous solubility of 489 ꢀM in
phosphate buffer (pH = 7.4) and over 9.5 mM in 0.1 HCl
solution. In rats, the plasma concentration of ABTꢀ639 was
increased proportionally in dose escalation at 30, 100 and 300
mg/kg. ABTꢀ639 has low protein binding (88.9% in rat and
85.2% in human). The brain to plasma concentration ratio was
1:20 in rats. ABTꢀ639 is a not a competitive inhibitor of
CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC50 > 10 µM). ABTꢀ
639 showed no CYP3A4 (PXR) induction (EC50 >10 µM), no
CYP1A2 mRNA induction (EC50 >10 µM).
are provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
ASSOCIATED CONTENT
Supporting Information
Experimental and characterization data for all compounds and
the Capsiacinꢀinduced secondary mechanical hyperalgesia assay
AUTHOR INFORMATION
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Corresponding Author
(11) Miwa, H.; Kondo, T. Tꢀtype calcium channel as a new
therapeutic target for tremor. Cerebellum. 2011, 10(3), 563ꢀ
569.
(12) Miwa, H.; Koh, J.; Kajimoto, Y.; Kondo, T. Effects of
Tꢀtype calcium channel blockers on a parkinsonian tremor
model in rats. Pharmacol Biochem Behav. 2011, 97(4), 656ꢀ
659.
(13) Yang, Z. Q.; Barrow, J. C.; Shipe, W. D.; Schlegel,
K.A.; Shu, Y.; Yang, F. V.; Lindsley, C. W.; Rittle, K. E.;
Bock, M. G.; Hartman, G.D.; Uebele, V. N.; Nuss, C. E.;
Fox, S. V.; Kraus, R. L.; Doran, S. M.; Connolly, T. M.;
Tang, C.; Ballard, J. E.; Kuo, Y.; Adarayan, E. D.;
Prueksaritanont, T.; Zrada, M. M.; Marino, M. J.; Graufelds,
V. K.; DiLella, A. G.; Reynolds, I. J.; Vargas, H. M.;
Bunting, P. B.; Woltmann, R. F.; Magee, M. M.; Koblan, K.
S.; Renger, J. J. Discovery of 1,4ꢀsubstituted piperidines as
potent and selective inhibitors of Tꢀtype calcium channels.
J. Med. Chem. 2008, 51, 6471–6477.
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*Eꢀmail: henry.zhang@abbvie.com.
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version.
Funding Sources
QZ, ZX, SJ, VES and MFJ are employees of AbbVie. The
research described herein is solely funded by AbbVie. AbbVie
contributed to the study design, research and interpretation of
data.
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ABBREVIATIONS
HTS, high throughput screening; VGCC, Voltageꢀgated calcium
channels, RLM, rat liver microsomes; HLM, human liver
microsomes; HTꢀADME, high throughputꢀabsorption,
distribution, metabolism, and excretion; FLIPR, fluorescent
imaging plate reader; EP, electrophysiology; DMF, N, N-
dimethylformamide, DRG, dorsal root ganglion; PK,
pharmacokinetics.
(14) PerezꢀReyes, E. Molecular physiology of lowꢀvoltageꢀ
activated tꢀtype calcium channels. Physiol Rev 2003, 83,
117ꢀ161.
(15) Bourinet, E.; Alloui, A.; Monteil, A.; Barrère, C.;
Couette, B.; Poirot, O.; Pages, A.; McRory, J.; Snutch, T. P.;
Eschalier, A.; Nargeot, J. Silencing of the CaV3.2 Tꢀtype
calcium channel gene in sensory neurons demonstrates its
major role in nociception. EMBO J 2005, 24, 315–324.
(16) Jagodic, M. M.; Pathirathna, S.; Joksovic, P. M.; Lee,
W.; Nelson, M. T.; Naik, A. K.; Su, P.; JevtovicꢀTodorovic,
V.; Todorovic, S. M. Upregulation of the Tꢀtype calcium
current in small rat sensory neurons after chronic constrictive
injury of the sciatic nerve. J Neurophysiol 2008, 99, 3151ꢀ
3156.
(17) Nelson, M. T.; Woo, J.; Kang, H. W.; Vitko, I.;
Barrett, P.Q.; PerezꢀReyes, E.; Lee, J. H.; Shin, H. S.;
Todorovic, S. M. Reducing agents sensitize Cꢀtype
nociceptors by relieving highꢀaffinity zinc inhibition of Tꢀ
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