Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.04.057

An increasing number of diseases have been linked to a dysfunctional peripheral serotonin system. Given that tryptophan hydroxylase 1 (TPH1) is the rate limiting enzyme in the biosynthesis off serotonin, it represents an attractive target to regulate peripheral serotonin. Following up to our first disclosure, we report a new chemotype of TPH1 inhibitors where-by the more common central planar heterocycle has been replaced with an open-chain, acyl guanidine surrogate. Through our work, we found that compounds of this nature provide highly potent TPH1 inhibitors with favorable physicochemical properties that were effective in reducing murine intestinal 5-HT in vivo. Furthermore, we obtained a high resolution (1.90 ?) X-ray structure crystal structure of one of these inhibitors (compound 51) that elucidated the active conformation along with revealing a dimeric form of TPH1 for the first time.

Full text of DOI:10.1016/j.bmcl.2016.04.057

Bioorganic & Medicinal Chemistry Letters 26 (2016) 2855–2860
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors
a
a
a
a
Daniel R. Goldberg a, , Stéphane De Lombaert , Robert Aiello , Patricia Bourassa , Nicole Barucci ,
⇑
Qing Zhang a, Vishwas Paralkar a, Adam J. Stein b, Jim Valentine a, William Zavadoski a
a Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States
b Cayman Chemical, 5025 Venture Dr., Ann Arbor, MI 48108, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An increasing number of diseases have been linked to a dysfunctional peripheral serotonin system. Given
that tryptophan hydroxylase 1 (TPH1) is the rate limiting enzyme in the biosynthesis off serotonin, it
represents an attractive target to regulate peripheral serotonin. Following up to our first disclosure, we
report a new chemotype of TPH1 inhibitors where-by the more common central planar heterocycle
has been replaced with an open-chain, acyl guanidine surrogate. Through our work, we found that com-
pounds of this nature provide highly potent TPH1 inhibitors with favorable physicochemical properties
that were effective in reducing murine intestinal 5-HT in vivo. Furthermore, we obtained a high resolu-
tion (1.90 Å) X-ray structure crystal structure of one of these inhibitors (compound 51) that elucidated
the active conformation along with revealing a dimeric form of TPH1 for the first time.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 22 January 2016
Revised 19 April 2016
Accepted 20 April 2016
Available online 21 April 2016
Keywords:
TPH1
Peripheral serotonin
5-HT
Medicinal chemistry
Acyl guanidine
Hydrophobic tail
Amino Acid Head
O
In recent years, an increasing number of diseases have been
linked to a dysfunctional peripheral serotonin system. Serotonin
(5-hydroxytryptamine, 5-HT) has been implicated in carcinoid
syndrome, various fibrotic diseases, non-alcoholic fatty liver
disease, obesity, atherosclerosis, allergic asthma, cancer, and pul-
monary arterial hypertension.1 The vasoconstrictive and mitogenic
properties of serotonin have been invoked to account for its patho-
physiological effects, but other secondary signaling pathways and
serotonylation processes may also be at play.2–4 While the exact
role of 5-HT in some of these diseases remains to be fully eluci-
dated, modulation of peripheral 5-HT tone and 5-HT overproduc-
tion in diseased tissues presents an attractive therapeutic
opportunity. Most of peripheral 5-HT is produced by enterochro-
maffin cells located in the gut and stored in platelets, with very
little circulating as free 5-HT. Serotonin does not cross the
blood–brain barrier, allowing the central and peripheral 5-HT sys-
tems to be regulated independently. Tryptophan hydroxylase 1
(TPH1), a member of the aromatic amino acid hydroxylase family,
is the rate limiting enzyme in the biosynthesis of peripheral 5-HT.
Selective TPH1 inhibition results in reductions of peripheral 5-HT
production. Therefore, TPH1 may serve as a molecular target for
intervention. Phenylalanine-derived TPH inhibitors devoid of
central nervous system exposure, have been reported to reduce
intestinal 5-HT concentration.5,14 Telotristat etiprate (LX-1606),
the ester prodrug of the potent TPH1 inhibitor LX-1033, is
Linker
F
OH
LP-533,401
NH2
O
CF3
N
N
NH2
HBA
Central Core
Cl
O
LX-1033
N
CF3
N
Figure 1. Critical pharmacophoric features as exemplified by LP-533,401 and LX-
1033. HBA = hydrogen bond acceptor.
currently in late stage Phase III clinical trials for the symptomatic
treatment of gastrointestinal symptoms associated with carcinoid
syndrome in patients who no longer respond to standard of care
medications.6–8 In this Letter, we disclose our discovery of novel
phenylalanine-derived TPH1 inhibitors.
Prior art and analysis of TPH1 X-ray structures show that a
number of peripherally restricted phenylalanine-derived TPH1
inhibitors match a pharmacophore model featuring three key areas
(Fig. 1).5,9,10,12
⇑
Corresponding author.
E-mail address: dgoldberg@kineta.us (D.R. Goldberg).
http://dx.doi.org/10.1016/j.bmcl.2016.04.057
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

2856
D. R. Goldberg et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2855–2860
Hydrophobic tail
Amino acid head
O
O
Linker
Linker
OH
OH
F
OH
H
N
N
E
NH2
O
NH2
R
HN
O
O
N
N
N
H
Central core
replacement
HBA
HBA
LP-533,401
NH2
O
O
OH
NH2
H2N
N
Z
H
NH2
N
N
N
H
R
HBA
HBA
Central core
Pseudo cycle
LP-534,193
Figure 2. Replacement of the central cores of LP-533,401 and LP-534,19310,12 with an open-chain acyl guanidine as a pseudo-cycle. Depending on the preferred E or Z
conformation of the acyl guanidine within the binding site, a 1,3 or 1,4 relationship between the amino acid head and the lipophilic tail would be achieved, respectively.
HBA = hydrogen bond acceptor.
Table 1
Table 2
Effect of acyl guanidine substitution on TPH1 inhibitory potency
Impact of substituent chain length connection and acyl guanidine N-methylation on
TPH1 inhibitory potency
O
O
OH
R2
H
OH
N
N
NH2
R
N
N
NH2
NH2
O
R1
HN
O
R3
R
TPH1 IC50 (nM)
R
TPH1 IC50 (nM)
R1
R2
H
R3
H
TPH1 IC50 (nM)
*
LP-533,401
180
3
165
*
6
61
*
*
1
2
H
20,000
11,036
4
5
405
*
3
H
H
H
H
H
165
599
*
2200
*
7
H
In addition to our initially disclosed proline based spirocyclic
class of TPH1 inhibitors,11 we also explored in parallel a variety
of structure-based designs aimed at changing either the amino acid
or central core regions. In this Letter, we report a new chemotype
of TPH1 inhibitors identified by removing or replacing aromatic
rings within the pharmacophore model. These modifications have
successfully introduced polar functionalities within the central
core, resulting in improved aqueous solubility for this class of
inhibitors.
We have replaced the central planar heterocycle with an
open-chain, acyl guanidine surrogate that was expected to achieve
conformational rigidity similar to planar heterocycles through
intramolecular H-bond between either of the NH groups and the
carbonyl, thereby forming a pseudo-cycle (Fig. 2). Since two con-
formers (E or Z) are possible, this was taken into account in the
design of the hydrophobic tail to provide an appropriate vector
to access this region irrespective of the conformation of the acyl
guanidine. In both conformations, the carbonyl would theoretically
be available to form the water mediated hydrogen bond to the iron
as observed in several published TPH1 crystal structures.11
Flexibility in the relative placement of the hydrophobic tail relative
to the amino acid head is achievable, as exemplified with
LP-533,401 and LP-534,193.12
*
8
H
974
*
*
9
Me
H
1625
2014
10
Me
devoid of any measurable TPH1 inhibition enzymatically. However,
through the addition of a benzyl group (2) measurable, albeit weak,
inhibitory activity was achieved (Table 1). This initial analog pro-
vided an attractive starting point for further optimization since
the benzyl ring offered three different positions to build from
and expand into the protein hydrophobic pocket. Since both LP-
533,401 and LP-534,193 feature different biphenyl arrangements,
One of our first attempts at was utilizing an unsubstituted acyl
guanidine (1), unfortunately this compound was unsurprisingly

D. R. Goldberg et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2855–2860
2857
Table 3
Table 5
Impact of N-benzyl substitution with 5-member heterocycles on TPH1 inhibitory
potency
Impact of piperidine substitutions and replacements on TPH1 inhibitory potency
O
O
OH
H
N
OH
N
NH2
H
N
N
NH2
R
R
NH2 O
NH2
O
R
TPH1 IC50 (nM)
R
TPH1 IC50 (nM)
R
TPH1 IC50 (nM)
R
TPH1 IC50 (nM)
*
*
*
N
N
LX-1033
16
13
14
15
666
N
21
22
23
11
26
27
28
38
N
N
*
*
11
335
501
1844
5107
N
N
N
*
*
*
*
N
N
15
20
45
54
N
N
N
N
N
*
*
12
N
N
N
Table 4
Impact of N-benzyl substitution on TPH1 inhibitory potency
O
*
*
*
OH
H
17
24
22
25
29
30
58
N
N
S
N
N
NH2
R
NH2
O
R
TPH1 IC50 (nM)
R
TPH1 IC50 (nM)
*
N
N
106
*
LX-1033
16
18
19
32
N
N
OH
*
*
*
*
*
N
O
N
O
25
33
31
106
16
17
16
22
99
N
*
20
129
N
N
6 was initially the most potent analog made, other two carbon
linkers were considerably weaker enzymatically (data not shown),
therefore, based on our model and for consistency, we utilized
compound 3 as our starting point to expand the SAR.
we probed the effect of adding a second phenyl ring in either the
ortho, meta or para positions independently. We were pleased to
discover that the enzymatic potency was significantly enhanced,
most notably by the addition of a phenyl group in the ortho posi-
tion. Indeed, 3 showed an IC50 on par with that of LP-533,401 mea-
sured in the same TPH1 enzyme assay.13
Replacement of the phenyl substituents with 5-membered
heterocycles, including a 3-methyl pyrazole (as in LX1606), consis-
tently had a deleterious effect on potency, suggesting a distinct
SAR pattern (Table 3).
However, the use of non-aromatic heterocyclic substituents led
to a number of potent compounds (Table 4).
Having established that the acyl guanidine linker, when substi-
tuted with the appropriately oriented hydrophobic group could
provide reasonable potency, we next assessed (a) the importance
on chain length and (b) the opportunities to build further from
the acyl guanidine core (Table 2). TPH1 inhibition could be
improved with a two carbon linker (6) while other chain lengths
simply eroded inhibitory potency. Additionally, nitrogen methyla-
tion independently on each of the acyl guanidine nitrogen atoms
also significantly reduced the inhibitors activity. While compound
Further structural exploration of the piperidine ring showed
that a variety of substituents were tolerated to some degree, but
in general, resulted in a loss in potency beyond a methyl group
(Table 5). Additionally, changing the piperidine to a morpholine
(31) or a thiomorpholine (29) were not favorable.
We turned next to modifications of the benzyl ring (Table 6). It
was clear from the SAR that substitution at either the C6 or C5
position were not only tolerated, but also resulted in significant
improvements in inhibitory potency. Most notably, the addition

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D. R. Goldberg et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2855–2860
Table 6
Table 7
Impact of aromatic ring substitution on TPH1 inhibitory potency
Impact of oxygen substitution on TPH1 inhibitory potency (piperidyl analogs)
R5
O
O
R4
R3
R6
OR
OH
OH
H
H
N
N
N
NH2
N
NH2
N
NH2 O
N
NH2 O
R3
H
R4
R5
R6
H
TPH1 IC50 (nM)
7
R
TPH1 IC50 (nM)
6
R
TPH1 IC50 (nM)
15
*
*
*
S
32
H
50
51
59
60
N
F3C
33
34
H
H
H
H
H
H
*
CF3
Me
11
12
*
*
6
6
15
16
Cl
35
H
H
H
14
OCH3
36
37
38
39
40
41
42
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
OMe
Me
H
H
16
17
18
22
22
25
33
*
*
CF3
OMe
H
H
H
Cl
*
52
61
H3CO
Cl
*
53
54
8
38 Me
18
26
43
H
H
H
34
*
*
*
10
62
44
45
46
47
48
49
OMe
Me
H
Cl
H
H
H
OMe
H
Me
Cl
H
H
H
H
H
H
H
H
H
H
H
H
35
46
61
66
69
74
OCH3
*
55
56
57
10
11
11
63 iPr
64
28
30
43
CF3
*
H
*
of smaller groups in the C6 position but also, surprisingly, larger
groups in the C5 position afforded potent TPH1 inhibitors, such
as 32.
65 Et
Cl
*
*
Given that substituents in both the C5 and C6 position could
improve potency, we looked to explore this region further, partic-
ularly having a functional handle with the O–R group (Table 7).
With 38 as a starting point, increasing size beyond a methyl group
quickly eroded both enzyme and cellular potency. We discovered
that, the addition of the phenoxy group (in an effort to explore
chemical space) which upon further elaboration could be further
improved to provide compounds with significant improvements
in enzymatic potency. With these new discoveries, we also applied
this to the azepane class as well (Table 8).
58
14
66
53
CF3
site, the acyl guanidine group binds as the Z-tautomer, thereby
adopting a 1,4 relationship between the hydrophobic tail and the
amino acid head. This pattern is distinct from the one featured in
LP-533,401 and LX-1033, and resemble more LP-534,193 (Fig. 2).
This Z-conformation, where the substituted amino group is
engaged preferentially in the intramolecular H-bond, is also
observed in the binding pose of other substituted acyl guanidine-
based enzyme inhibitors.14,15 Additionally, the carbonyl of the acyl
guanidine forms a second, intermolecular H-bond with the pheno-
lic hydroxyl of Y235, pulling the flexible tyrosine side-chain
Within a few analogs, we established that the SAR translated to
the azepane-substituted derivatives (Table 8).
Synthetically, the compounds are made in a step wise fashion
from L-tyrosine methyl ester as outlined in Schemes 1 and 2.
Specifically, N-Boc protection of the tyrosinate amino group, fol-
lowed by triflation and carbonylation provided (S)-4-(2-((tert-
butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)benzoic acid (E).
EDCI/HOAt-mediated coupling with S-methylisothiouronium sul-
fate provides the required Key Intermediate A. As noted in
Scheme 2, the acyl guanidines were synthesized by reacting A with
an appropriate amine, upon which ester saponification and N-Boc
removal provides the final product 17). The complete synthetic
details are provided in the Supplemental material.13
Based on its high intrinsic potency and extended substitution
pattern, 51 was selected as an interesting representative of this
new class of TPH1 inhibitors for further structural analysis. A
1.90 Å resolution X-ray structure of 51 bound to TPH1 was
obtained via co-crystallization (see Supplemental material) and
confirmed our fundamental binding hypothesis that the acyl
Table 8
Impact of oxygen substitution on TPH1 inhibitory potency (azepanyl analogs)
O
OR
OH
H
N
N
NH2
N
NH2 O
R
TPH1 IC50 (nM)
*
67
68
13
19
guanidine moiety acts effectively as
a pseudo-cycle via an
Me
intramolecular H-bond (PDB ID: 5J6D, Fig. 3). Within the active

D. R. Goldberg et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2855–2860
2859
O
O
O
(Boc)2O
Tf2O
OMe
OMe
NHBoc
OMe
NHBoc
NH2
NaHCO3
THF/MeOH
90%
Pyridine
0 oC -> RT
70%
HO
HO
TfO
C
B
D
O
O
OMe
OMe
NHBoc
Pd(OAc)2
EDCI, HOAt
NH
MeS
N
NHBoc
HO
NH2
O
dppf, KOAc
CO, 60 o
O
C
E
H2N
SMe . H2SO4
Intermediate A
35% (two steps)
Scheme 1. Synthesis of Key Intermediate A.
O
O
OMe
NHBoc
H
N
Et3N
OMe
NHBoc
NH2
N
+
MeS
N
Δ
N
NH2
O
N
O
NH2
85%
G
Intermediate A
F
O
O
OH
NHBoc
OH
H
N
H
TFA
90%
LiOH
100%
NH2
N
N
N
O
O
NH2
NH2
N
N
17
H
Scheme 2. Synthesis of representative acyl guanidine.
Unlike previously reported and our other unpublished X-ray
structures, the co-crystal of 51 bound to TPH1 exists as a dimer
(Fig. 4). Monomer A is more ordered than monomer B, presumably
due to a much lower population of dimeric molecules. Interest-
ingly, the N-terminal residues M102-T104 of monomer B appear
to hinder access to the active site on monomer A, trapping the
bound inhibitor.
Having established the usefulness of the polar acyl guanidine
linker to achieve potent TPH1 inhibition, we examined the impact
of these drastic structural changes on the physicochemical and
efficacy attributes of these compounds. As anticipated, acyl
guanidine-based TPH1 inhibitors displayed improved physico-
chemical properties relative to LP-533,401. For example, the
kinetic aqueous solubility of 51 at pH 7.4 exceeded 40
LP-533,401 was at least an order of magnitude less soluble
(2.1 M) as measured via kinetic solubility of test compound in
50 mM phosphate buffer (pH 7.4). As a note, compounds from this
series in general have higher kinetic solubility (e.g. 35 = 16 M;
68 = 40 M) versus the heterocyclic core moieties. Comparing both
lM, while
l
Figure 3. Key binding interactions between the potent acyl guanidine-containing
inhibitor 51 within the TPH1 active site. Contact residues are shown in blue text.
Ligand–protein H-bond interactions are represented with hashed cyano lines. The
intramolecular H-bond forming a pseudo-cycle is depicted as a green hashed line.
The figure was produced with Tripos Benchware 3D Explorer.
l
l
compounds, 51 also showed lower plasma protein binding (rat)
(equilibrium dialysis) 88% versus > 99.9%, respectively.
Several acyl guanidine-based TPH1 inhibitors were screened
in vivo in mice to assess their ability to reduce mucosal serotonin
levels. As also demonstrated with Telotristat etiprate and with our
spirocyclic proline-derived TPH1 inhibitors,11 the corresponding
ethyl ester prodrugs provided enhanced in vivo activity compared
to the parent drugs, as exemplified with the drug/prodrug 7pairs
68/69 and 62/70 (Table 9).12,15
In conclusion, we have described a new series of acyl guanidines
displaying potent TPH1 inhibition, increased aqueous solubility,
and efficacy in reducing intestinal 5-HT in vivo. A crystal structure
slightly closer to the ligand, compared to LP-533,401 (PDB ID:
3HF8) and LP-534,193 (PDB ID: 3HFB). Consequently, contrary to
our original design hypothesis, the carbonyl oxygen points away
from the conserved water molecule bound to the iron atom.
Instead, the imino nitrogen of the acyl guanidine overlays with
the H-bond acceptor nitrogen featured in heterocyclic core-con-
taining TPH1 inhibitors. Other H-bond interactions between 51
and the E317, T265, and R257 residues are similar to those
achieved with LP-533,401.

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D. R. Goldberg et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2855–2860
Figure 4. Dimeric X-ray structure of 51-bound TPH1. Each monomer contains a distinct ligand of identical binding conformation. The N-terminal residues M102-T104 of
monomer B shows interactions between the monomers in close proximity to the active site. The figure was produced with Tripos Benchware 3D Explorer.
Table 9
References and notes
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Acknowledgements
The authors would like to thank Shanghai ChemPartner and
Santai Labs for their assistance in preparing synthetic intermedi-
ates and/or final compounds.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.04.
057.