Optimization of Novel Antagonists to the Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part II)

Article abstract of DOI:10.1021/acsmedchemlett.5b00117

Further lead optimization on N-acyl-triazolopiperazine antagonists to the neurokinin-3 receptor (NK₃R) based on the concurrent improvement in bioactivity and ligand lipophilic efficiency (LLE) is reported. Overall, compound 3 (LLE > 6) emerged as the most efficacious in castrated rat and monkey to lower plasma LH, and it displayed the best off-target safety profile that led to its clinical candidate nomination for the treatment of sex-hormone disorders.

Full text of DOI:10.1021/acsmedchemlett.5b00117

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Letter
pubs.acs.org/acsmedchemlett
Optimization of Novel Antagonists to the Neurokinin‑3 Receptor for
the Treatment of Sex-Hormone Disorders (Part II)
Hamid R. Hoveyda,* Graeme L. Fraser, Guillaume Dutheuil, Mohamed El Bousmaqui, Julien Korac,
Franco̧ is Lenoir, Alexey Lapin, and Sophie Noel
̈
Euroscreen SA, 47 rue Adrienne Bolland, 6041 Gosselies, Belgium
S
* Supporting Information
ABSTRACT: Further lead optimization on N-acyl-triazolopiperazine antagonists
to the neurokinin-3 receptor (NK3R) based on the concurrent improvement in
bioactivity and ligand lipophilic efficiency (LLE) is reported. Overall, compound 3
(LLE > 6) emerged as the most efficacious in castrated rat and monkey to lower
plasma LH, and it displayed the best off-target safety profile that led to its clinical
candidate nomination for the treatment of sex-hormone disorders.
KEYWORDS: NK3 antagonist, triazolopiperazine, neurokinin B, LH, FSH, GnRH
versus follicle-stimulating hormone (FSH). Thus, high
he neurokinin-3 receptor (NK3R) is a class A GPCR with
Tneurokinin B (NKB) as its endogenous agonist. We frequency pulses stimulate LH release, whereas low frequency
pulses favor FSH induction.4 These gonadotropins ultimately
act on the ovary and testis to promote production of gametes
present here the sequel on the lead optimization of N-acyl-
triazolopiperazine NK3R antagonists (1 and 2, Figure 1).1
and sex-hormone release. In 2011, it was reported that patients
with a loss of function mutation in NK3R display a phenotype
of normosomic congenital hypogonadotropic hypogonadism,
low plasma LH, and attendant low LH/FSH ratios that could
be restored through exogenous administration of GnRH.5 We
have demonstrated elsewhere6 that the foregoing NK3R
antagonists slow the LH pulse and decrease circulating LH
levels without affecting FSH, consistent with the literature
reports.4 As such, these antagonists are subtle modulators of
gonadotropin secretion unlike GnRH ligands that abrogate
both LH and FSH with the consequent decline in plasma
estrogen to castration levels thereby triggering menopausal-like
adverse events such as bone mineral density loss and incidences
of hot flashes.7 Hence, NK3R antagonists offer a potentially
safer therapeutic approach due to a decreased rather than
abrogated GnRH pulse frequency. Collectively, these findings
offer a strong rationale for repositioning NK3R antagonists to
address sex-hormones disorders such as polycystic ovary
syndrome (PCOS) and uterine fibroids (UF), among others.8
The synthetic approach to the analogues herein was
previously described.1 With minor modifications, Scheme 1
was used for the GMP scale-up of 3 in overall 42% yield (2.7
kg) with 99.3% purity and >99.9% enantiomeric excess.
Figure 1. Lead progression: iv POC (1), oral POC (2), and clinical
candidate (3). (The “magic methyl” groups are shown in red.)
NK3R antagonists were speculated as therapeutically relevant
for CNS dysfunctions, e.g., schizophrenia, predicated on the
“hyperdopaminergic hypothesis”, which repeatedly met with
clinical failures in over a decade of efforts.2 Meanwhile,
emerging biology has unambiguously established the role of
NK3R/NKB signaling in reproductive neuroendocrinology.
Importantly, recent studies have revealed NK3R as a key
regulatory component of the hypothalamic−pituitary−gonadal
(HPG) axis wherein its tonic activation positively regulates the
gonadotropin-releasing hormone (GnRH) pulse frequency.3 In
turn, the GnRH pulse frequency is known to differentially
control the circulating levels of luteinizing hormone (LH)
Received: March 17, 2015
Accepted: May 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00117
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ACS Medicinal Chemistry Letters
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a
Interestingly, a hydroxyethyl substitution at Ring B (18)
afforded an alternative means of reducing lipophilicity
(ΔlogD7.4 = −0.5 vs 3) with minimal impact on bioactivity,
thus resulting in a 0.4-log superior LLE vs 3. Despite this, 18
proved inferior to 3 due to Pgp efflux that in turn markedly
diminished its brain exposure level (Table 2 and discussion
further below).
Scheme 1
The hERG SAR herein (Table 1) was governed by the
interplay between lipophilicity and the hydrogen-bond acceptor
(HBA) count in the heteroaryl Ring D, as previously reported.1
For instance, in progressing from 8 to 3 (ΔlogD7.4 = 1.5), the
hERG IC50 was improved by over 12-fold. However, the poor
hERG IC50 = 1.6 μM in 11 (logD7.4 = 1.7) was in keeping with
the increased HBA count in the Ring D oxadiazole (N + N +
O) in stark contrast to the thiadiazole (N + N) Ring D
variations (3 and 15−18), all of which displayed a superior
hERG, IC50 ≥ 39 μM (logD7.4 = 1.3−2.4). Interestingly, the
Ring B hydroxyl group in 18 did not adversely impact hERG
(IC50 = 50 μM) suggesting that the HBA effect on hERG SAR
is primarily a Ring D related effect. Finally, the Ring B magic
methyl also reduced hERG efficacy, i.e., 3 (IC50 > 100 μM) vs
12 (IC50 = 50 μM). Compound 3 was the best overall in the
hERG and CYP safety profile evaluation.
a
Reagents and conditions: (a) Et3OBF4, Na2CO3, CH2Cl2, 45 min,
68%; (b) MeOH, 70 °C, 8 h, 80%; (c) TFA, 2 h, >99% conversion;
(d) 4-fluorobenzoyl chloride, NaHCO3, 15 min, 97%; (e) recrystal-
lization (EtOH/H2O), 97% (DMB = 2,4-dimethoxybenzyl).
The in vitro bioactivity structure−activity relationship (SAR)
was established through radioligand binding (pKi) and aequorin
functional assays (pIC50) data from recombinant human NK3R
in CHO cells. The lead optimization strategy1 of combined
improvement in both bioactivity and ligand lipophilic efficiency
(LLE = pKi − logD7.4)9 was maintained. An initial emphasis
was placed on LLE as a predictive marker of improved safety
profiles.10 Other efficiency metrics such as LE11 and Fsp3
12
Based on the free drug hypothesis, the unbound fraction
rather than total drug is relevant for PKPD analysis.15 The
NK3R is mainly expressed on KNDy neurons in the ARC
region of the hypothalamus3 that is part of the circum-
ventricular organs lacking blood−brain barrier and are therefore
exposed to blood solutes.16 As such, both the unbound plasma
(fu) and the unbound brain levels (bfu) must be considered
here (Table 2). While lipophilicity alone does not correlate well
to albumin binding, this trend is often apparent in a congeneric
series.17 Hence, a compound with balanced lipophilicity such as
3 (logD7.4 = 1.5) displayed high fu and bfu levels (>50%) in
contrast to the more lipophilic congeners, e.g., 16 (Table 2). It
is noteworthy that despite an increase in unbound plasma
concentration, the systemic clearance levels (CLT) remained
low (e.g., 3, Table 2). The comparatively lower CLT in para
substituted phenyl Ring A (3, 15) against the unsubstituted
congener 17 is likely due to the metabolic blocking effect. All
analogues except 18 displayed high Caco-2 permeability with
no evidence of appreciable Pgp efflux (ER = 0.6−1.2),
consistent with the high oral availability (%F) and brain-to-
plasma ratios observed. The so-called Pgp rule-of-4 suggests that
increasing the number of HBA atoms to (N + O) ≥ 8 tends to
confer an increasing likelihood of Pgp efflux.18 This is in keeping
with the Pgp efflux in 18 (ER = 3.8) given its HBA atom count
(N + O = 8). As with 2,1 a complete oral absorption (%F >
100) was also observed in rat with compound 12 and in
monkey with 3. This phenomenon is well-known and various
underlying causes have been reported.19 No drug accumulation
was observed in 5-day once-daily oral dosing studies in rats (3
and 12) or monkeys (3), despite administration of elevated
doses (e.g., up to 1 g/kg in rats with 12), in step with the
relatively short half-life values and the previous related
observations with 2.1 Moreover, no adverse hepatotoxicity
(AST, ALT, and bilirubin levels normal) was detected in these
subchronic studies. Furthermore, 3 displayed the highest bfu =
0.525 and brain unbound concentration (Cbrain,u = 343 nM)
herein (Table 2). In contrast, 18 although nearly completely
(Table 1) were also tracked, though not as a primary focus. The
previously discovered “magic methyl” groups in Rings B and D
(Figure 1),1 so-called due to their significant impact in
improving potency and LLE, remained crucial and rendered
feasible improvements in Fsp3 and LE as well (see below).
To recall, replacing 2-methylthiazole (2) at Ring D with 3-
methyl-1,2,4-thiadiazole (8) was reported earlier to markedly
improve bioactivity and LLE (Table 1).1 Moreover, 1,2,4-
thiadiazole is regarded as a means of circumventing
bioactivation liabilities potentially relevant to the thiazole
ring.13 These considerations overall prompted us to retain the
1,2,4-thiadiazole, but to modify the 4-(thiophen-2-yl)phenyl in
8 to the 4-fluorophenyl Ring A (i.e., 3) present in the earlier
lead structures.1 Progression from 8 to 3 helped reduce
lipophilicity (ΔlogD7.4 = −1.5), which not surprisingly right-
shifted bioactivity by nearly one log. However, in evaluating 3
against 8, the improved LLE and absence of the thiophene ring
(a potential structural safety alert)14 was considered of greater
importance due to the reduced toxicological risk. In addition, 3
was nearly equipotent to the oral POC lead 2, while >1-log
superior in LLE. Narrowing our focus on the thiadiazole Ring
D and related variants, we observed the following descending
trend in bioactivity (Table 1): 1,2,4-thiadiazole (3) > 1,2,4-
oxadiazole (10) ≫ 1,3,4-thiadiazole (9). As with the Ring A
cases, increased lipophilicity in Ring D helped improve
bioactivity albeit offset by a loss in LLE, e.g., 11 vs 10 (Table
1). The impact of Rings B and D magic methyl groups on SAR
trends was quite pronounced, as expected based on previous
results,1 since the corresponding des-Me analogues of 3,
whether at Ring B or D (12 and 13, respectively), were
decidedly inferior in both bioactivity and LLE (Table 1). Gem
dimethyl Ring B substitution substantially eroded the
bioactivity (14 vs 3) in keeping with the unfavorable impact
of (S)-Me at this Ring B position (data not shown).1 Once
again, improved bioactivity followed increased lipophilicity
whether at Ring A (15) or at Ring D (16) positions, but this
gain was negated by a deteriorated LLE against 3. Conversely,
replacing 4-fluorophenyl with phenyl at Ring A, i.e., 17, helped
diminish lipophilicity, but it also deteriorated bioactivity.
unbound in the brain displayed a comparatively low Cbrain,u
45.6 nM consistent with its elevated Pgp efflux ratio.
=
B
DOI: 10.1021/acsmedchemlett.5b00117
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Table 1. Human NK3R In Vitro Bioactivity, LogD7.4, Ligand Efficiency Metrics,10−12 and Off-Target Safety SAR
a
b
c
N = 3, %RSD ≤ 5. CYP 3A4, 2D6, 2C9, 2C19, and 1A2, respectively (N = 2, <10% variability). N = 3, coefficient of variation < 6%.
The key PKPD parameters for interpreting the LH inhibition
superiority of 3 vs 2 underscores the greater unbound exposure
levels and consequently the greater in vivo efficacy of 3.
Likewise, the monkey LH data (Figure 2) mirrored these trends
with 3 4-fold more efficacious (MED levels) although nearly
equipotent to 2 in monkey Ki values (Table 3) in keeping with
the significantly better MED-normalized plasma PKPD
parameter for 3 vs 2.
In summary, 3 proved a superior lead candidate based on
bioactivity, LLE, LE, and Fsp3 (Table 1) criteria. Apart from its
excellent hERG and CYP safety profile, 3 was highly efficacious
in LH inhibition, showed >2.5-log selectivity against NK1R and
NK2R subtypes, proved >300-fold selective against related HPG
axis receptors1 (KOR, GnRH, GnIH-R, GPR54), and was
highly selective in the broad CEREP off-target screen (<25%
data are the unbound plasma and brain levels normalized with
respect to the bioactivity, i.e., Cplasma,u/Ki and Cbrain u/Ki (Table
3).1 The plasma and brain levels were determined at the Tmax
for the minimum effective dose (MED). As noted before for 2
and 8,1 a statistically significant effect was attained at Cplasma,u/Ki
≥ 7.6 and Cbrain,u/Ki > 1 in rat oral LH inhibition studies. This
was also the case here, i.e., for analogues 3, 12, and 16−18, with
MED values ranging from 3 mg/kg (3) to 30 mg/kg (12 and
17). For example, in rats, 3 was 20-fold more efficacious in vivo
against the initial POC lead 2 despite being 3-fold right-shifted
in Ki. This ameliorated efficacy is reflected in their respective
MED-normalized plasma and brain PKPD parameters (Table 3,
the last two columns). Otherwise stated, the >1-log LLE
C
DOI: 10.1021/acsmedchemlett.5b00117
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a
Table 2. Permeability, Plasma and Brain Fraction Unbound, Brain Exposure, and PK Data
Caco-2 Papp
(nm/sec)
plasma
fu
brain
fu
Cplasma,u
(nM)
Cbrain,u
(nM)
iv ClT
(min/mL/kg)
iv Vss
(L/kg)
iv T1/2
(min)
Cpd
AB
BA
ER
species
(B/P)u
%F
b
2
339
−
487
224
−
465
0.7
−
1.0
rat
0.055
0.043
0.639
0.532
0.065
0.674
0.408
0.291
0.592
0.662
0.028
−
0.525
54.4
17.9
1507
5040
58.6
1767
−
348.0
406.7
897.4
7.79
−
343
0.14
−
0.23
7.4
1.4
126
210
279
324
267
239
294
1479
35
119
12
c
2
monkey
rat
16.5
1.5
1.52
0.60
1.15
2.8
b
3
62.5
107
−
126
73.6
98.2
55
c
3
−
−
−
monkey
rat
−
−
−
3.17
7.3
d
8
360
477
467
419
437
91
221
528
345
368
519
345
0.6
1.1
0.7
0.9
1.2
3.8
0.031
0.436
−
0.109
0.604
0.995
39.3
212
−
85.4
68.6
45.6
0.67
0.12
−
0.25
0.17
0.05
d
12
rat
1.94
2.2
0.65
0.91
2.25
0.68
1.59
d
15
rat
d
16
rat
1.07
13.7
5.07
d
17
rat
d
18
rat
215
46.6
a
PK doses: iv, 1 mg/kg (rat), 10 mg/kg (monkey); oral, 3 mg/kg (rat), 5 mg/kg (monkey). Brain exposure dose: 1 mg/kg. Mean values for N = 3−4
rats, or 4 monkeys, per group. All rat data at 60 min: (B/P)u = Cbrain,u/Cplasma, u with Cbrain,u = Cbrain, total × bfu and Cplasma,u = Cplasma,total × fu. Monkey
b
c
d
Cplasma,u data at 90 min (oral). PK formulation: HPβCD. PK formulation: iv HPβCD; oral 0.5% MC/water. PK formulation: 1% DMSO, HPβCD
in 0.9% NaCl.
a
Table 3. PKPD Analysis of the Oral LH Inhibition Studies
Cpd
species
Ki (nM)
LLE
MED (mg/kg)
Tmax (min)
Cplasma,u/Ki
Cbrain,u/Ki
(Cplasma,u/Ki)/MED
(Cbrain,u/Ki)/MED
2
rat
76
4.0
4.6
5.2
6.1
4.6
4.5
4.7
4.9
5.6
60
20
3
150
60
16.4
13.3
22.0
192
2.32
−
5.03
0.273
0.665
7.33
38.4
1.5
0.039
−
1.68
2
monkey
rat
20
3
219
25
150
90
3
monkey
rat
5
−
−
8
22
10
30
10
30
10
150
150
150
45
15.0
22.5
23.8
47.3
38.9
12.4
2.77
5.87
7.71
1.82
1.24
0.09
0.59
0.26
0.18
12
16
17
18
rat
2033
85
0.75
2.38
1.58
3.89
rat
rat
573
244
rat
45
a
Plasma concentrations coincident with LH measurements. MED determined by a significant decrease (p < 0.05) in LH vs baseline with a lower
nonsignificant dose established in all cases.
Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00117.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hhoveyda@euroscreen.com. Tel: +32-71.348.502.
■
Funding
This work was supported by the Ministry of Sustainable
Development and Public Works, Walloon Region, Belgium.
Notes
The authors declare no competing financial interest.
Figure 2. Oral LH inhibition with 3 (0.5% MC/water) in castrated
cynomolgus monkey (2-way ANOVA and Dunnet’s comparison to the
vehicle; ***p < 0.001, **p < 0.01).
ACKNOWLEDGMENTS
We thank Prof. Tony Plant and Dr. Suresh Ramaswamy
(University of Pittsburgh) for the monkey LH assays.
■
inhib at 10 μM). Finally, 3 showed no effect either in
Langendorff cardiac safety in rabbits (up to 30 μM) or in
AMES genotoxicity test (up to 100 μM). Compound 3
(ESN364) is currently in phase 2 clinical trials for the treatment
of PCOS and UF.
ABBREVIATIONS
■
ARC, arcuate nucleus; AST, aspartate transaminase; ALT,
alanine aminotransferase; bfu, brain fraction unbound; (B/P)u,
unbound brain-to-plasma; CYP, cytochrome P-450; FSH,
follicle-stimulating hormone; Fsp3, fraction sp3 carbon content;
fu, plasma fraction unbound; GnRH, gonadotropin-releasing-
hormone; HBA, hydrogen-bond acceptor; hERG, human ether-
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details for the synthesis and characterization of
compounds, X-ray structure of 3 (accession code: CCDC
1052911), and pharmacology and profiling assays. The
̀
a-go-go related gene; HPβCD, 9% hydroxypropyl-β-cyclo-
dextrin; HPG, hypothalamic−pituitary−gonadal; KNDy, kiss-
peptin-neurokinin B-dynorphin A neuron; LH, luteinizing
D
DOI: 10.1021/acsmedchemlett.5b00117
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ACS Medicinal Chemistry Letters
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(17) Kratochwil, N. A.; Huber, W.; Muller, F.; Kansy, M.; Gerber, P.
R. Predicting plasma protein binding of drugs: a new approach.
Biochem. Pharmacol. 2002, 64, 1355−1374.
(18) Kerns, E. H.; Di, L. Drug-like Properties: Concepts, Structure
Design and Methods: from ADME to Toxicity Optimization; Elsevier:
Burlington, MA, 2008; pp 112−116.
(19) For example, see: Godbole, A. M.; Ramalingam, S.;
Ramamurthy, V. P.; Khandelwal, A.; Bruno, R. D.; Upreti, V. V.;
Gediya, L. K.; Purushottamachar, P.; Mbatia, H. W.; Addya, S.;
Ambulos, N.; Njar, V. C. O. VN/14−1 induces ER stress and
autophagy in HP-LTLC human breast cancer cells and has excellent
oral pharmacokinetic profile in female Sprague-Dawley rats. Eur. J.
Pharmacol. 2014, 734, 98−104 and references therein.
hormone; LE, ligand efficiency; LLE, ligand lipophilicity
efficiency; MC, methyl cellulose; MED, minimum effective
dose; NKB, neurokinin B; NK3R, neurokinin-3 receptor; Pgp, P-
glycoprotein; PKPD, pharmacokinetic−pharmacodynamic;
POC, proof-of-concept; T1/2, elimination half-life; Vss, steady-
state volume of distribution
REFERENCES
■
(1) Hoveyda, H. R.; Fraser, G. L.; Roy, M.-O.; Dutheuil, G.; Batt, F.;
El Bousmaqui, K. J.; Lenoir, F.; Lapin, A.; Noel, S.; Blanc, S. Discovery
̈
and optimization of novel antagonists to the human neurokinin-3
receptor for the treatment of sex-hormone disorders (Part I). J. Med.
Chem. 2015, 58, 3060−3082 (Cpds 1, 2, and 8 were reported in ref 1
as 3, 31, and 39, respectively.).
(2) Dawson, L. A.; Porter, R. A. Progress in the development of
neurokinin 3 modulators for the treatment of schizophrenia: molecule
development and clinical progress. Future Med. Chem. 2013, 5, 1525−
1546 and references therein.
(3) For a recent review, see: Skorupskaite, K.; George, J. T.;
Anderson, R. A. The kisspeptin-GnRH pathway in human
reproductive health and disease. Hum. Reprod. Update 2014, 0, 1−16.
(4) Marshall, J. C.; Griffin, M. L. The role of changing pulse
frequency in the regulation of ovulation. Hum. Reprod. 1993, 8, 57−61.
(5) Francou, B.; Bouligand, J.; Voican, A.; Amazit, L.; Trabado, S.;
Fagart, J.; Meduri, G.; Brailly-Tabard, S.; Chanson, P.; Lecomte, P.;
Guiochon-Mantel, A.; Young, J. Normosomic congenital hypogonado-
tropic hypogonadism due to TAC3/TACR3 mutations: character-
ization of neuroendocrine phenotypes and novel mutations. PLoS One
2011, 6, e25614.
(6) Fraser, G. L.; Hoveyda, H. R.; Clarke, I. J.; Ramaswamy, S.; Plant,
T. M.; Rose, C.; Millar, R. P. The NK3 receptor antagonist ESN364
interrupts pulsatile LH secretion and moderates levels of ovarian
hormones throughout the menstrual cycle. Endocrinology, submitted
for publication.
(7) Riggs, M. M.; Bennets, M.; van der Graaf, P. H.; Martin, S. W.
Integrated pharmacometrics and systems pharmacology model-based
analysis to guide GnRH modulator development for management of
endometriosis. CPT: Pharmacometrics Syst. Pharmacol. 2012, 1, e11.
(8) Millar, R. P.; Newton, C. L. Current and future applications of
GnRH, kisspeptin and neurokinin B analogues. Nat. Rev. Endocrinol.
2013, 9, 451−466 and references therein.
(9) Hopkins, A. L.; Keseru, G. M.; Lesson, P. D.; Rees, D. C.;
̈
Reynolds, C. H. The role of ligand efficiency metrics in drug discovery.
Nat. Rev. Drug Discovery 2014, 13, 105−121 and references therein.
(10) Leeson, P. D.; Empfield, J. R. Reducing the risk of drug attrition
associated with physicochemical properties. Annu. Rep. Med. Chem.
2010, 45, 381−391 and references therein.
(11) LE = (1.37/HAC) × pKi. HAC = number of non-hydrogen
atoms (ref 9).
(12) Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland:
increasing saturation as an approach to improving clinical success. J.
Med. Chem. 2009, 52, 6752−6756.
(13) Kalgutkar, A. S.; Driscoll, J.; Zhao, S. X.; Walker, G. S.; Shepard,
R. M.; Soglia, J. R.; Atherton, J.; Yu, L.; Mutlib, A. E.; Munchhof, M. J.;
Reiter, L. A.; Jones, C. S.; Doty, J. L.; Trevena, K. A.; Shaffer, C. L.;
Ripp, S. L. A rational chemical intervention strategy to circumvent
bioactivation liabilities associated with a nonpeptidyl thrombopoietin
receptor agonist containing a 2-amino-4-arylthiazole motif. Chem. Res.
Toxicol. 2007, 20, 1954−1965.
̌ ̌
(14) Gramec, D.; Masic, L. P.; Dolenc, M. S. Bioactivation potential
of thiophene-containing drugs. Chem. Res. Toxicol. 2014, 27, 1344−
1358 and references therein.
(15) Trainor, G. L. The importance of plasma protein binding in
drug discovery. Expert Opin. Drug Discovery 2007, 2, 51−64 and
references therein.
(16) Morita, S.; Miyata, S. Accessibility of low-molecular-mass
molecules to the median eminence and arcuate hypothalamic nucleus
of adult mouse. Cell Biochem. Funct. 2013, 3, 668−677.
E
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