Identification of RO4597014, a glucokinase activator studied in the clinic for the treatment of type 2 diabetes

Article abstract of DOI:10.1021/ml400027y

To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.

Full text of DOI:10.1021/ml400027y

Letter
pubs.acs.org/acsmedchemlett
Identification of RO4597014, a Glucokinase Activator Studied in the
Clinic for the Treatment of Type 2 Diabetes
Yimin Qian,*,† Wendy L. Corbett,† Steven J. Berthel,† Duk Soon Choi,‡ Mark T. Dvorozniak,§
Wanping Geng,∥ Paul Gillespie,† Kevin R. Guertin,† Nancy-Ellen Haynes,† Robert F. Kester,†
Francis A. Mennona,† David Moore,∥ Jagdish Racha,∥ Roumen Radinov,⊥ Ramakanth Sarabu,†
Nathan R. Scott,† Joseph Grimsby,§ and Navita L. Mallalieu#
‡
§
∥
†Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug
⊥
#
Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche, 340 Kingsland Street, Nutley,
New Jersey 07110, United States
S
* Supporting Information
ABSTRACT: To resolve the metabolite redox cycling
associated with our earlier clinical compound 2, we carried
out lead optimization of lead molecule 1. Compound 4
showed improved lipophilic ligand efficiency and demon-
strated robust glucose lowering in diet-induced obese mice
without a liability in predictive preclinical drug safety studies.
Thus, it was selected as a clinical candidate and further studied
in type 2 diabetic patients. Clinical data suggests no evidence
of metabolite cycling, which is consistent with the preclinical profiling of metabolism.
KEYWORDS: Glucokinase activator, type 2 diabetes, lipophilic ligand efficiency, metabolite, redox cycling
lucokinase (GK) catalyzes the phosphorylation of glucose
Gto glucose-6-phosphate. GK is widely accepted as a
glucose sensor, and compounds that activate GK could lead to a
potential therapy for type 2 diabetes.1 Since our discovery of
phenylacetamides as potent allosteric GK activators,2,3 GK
activators (GKAs) with chemical structures closely related to
the phenylacetamide scaffold or from completely different
chemical classes have been reported.4−12 Recently, we reported
that 1, a lead molecule with robust in vivo efficacy, inactivated
cytochrome P450 3A4 (CYP3A4) in a time-dependent manner,
̀
blocked the human-Ether-a-go-go-Related Gene (hERG)
Figure 1. Chemical structures of 1−4.
potassium channel and increased the duration of the action
potential in the rabbit Purkinje fiber assay. After extensive
metabolite profiling of 1 from in vitro and in vivo studies, 2
(Piragliatin) was identified as an active metabolite without the
liability of hERG inhibition or CYP3A4 time-dependent
inactivation (TDI).13 This molecule was further developed
and evaluated in diabetic patients.
Although replacing the cyclopentane moiety in 1 with a
cyclopentanone in 2 resolved issues of hERG inhibition and
CYP3A4 inactivation, 2 was observed to undergo ketone/
alcohol redox cycling between 2 and 3 (Figure 1) from both in
vitro and in vivo metabolism studies. In searching for a backup
molecule, our goal was to identify potent GK activators in the
aminopyrazine phenylacetamide chemical class devoid of
metabolite cycling. Herein, we report our lead optimization
of 1, which culminated in the identification of 4 (RO4597014),
a potent GK activator that entered clinical studies in type 2
diabetic patients.
In order to resolve the issue of metabolite cycling between 2
and 3, we initially focused on the modification of the cycloalkyl
side chain. As illustrated in Table 1, significant loss of GK
activation potency (SC1.5, stimulation concentration required to
achieve GK activity 150% of the control) was observed when
the cyclopentane fragment was replaced with 4-tetrahydropyran
or 3-tetrahydrofuran (7 and 8). To resolve the hERG inhibition
and CYP3A4 inactivation associated with 1, we investigated less
hydrophobic groups at the R1 and R2 positions. However,
these modifications caused a decrease in GK activation potency
(compound 6 in Table 1, and compounds 42−49 in Table S1
of the Supporting Information). Structure−activity relation-
ships (SARs) from Table 1 and Table S1, Supporting
Received: January 23, 2013
Accepted: March 7, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ml400027y | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
Table 1. GK Activation Potency, Effects on Inactivating CYP3A4, Inhibition of hERG, and in Vivo Efficacy in Lowering Blood
Glucose in C57 Mice by Compounds 1, 4, and 6−24
a
SC1.5: compound concentration required to achieve GK activity 150% of control, numbers are the average from at least three independent assays,
b
the average CV of the assay was 15% based on data analysis of over 400 compounds with SC1.5 < 2 μM. Percentage of inhibition of hERG
potassium channel at a compound concentration of 10 μM; numbers are the average from at least three measurements. Time-dependent
c
inactivation (TDI) of CYP3A4 at a compound concentration of 10 μM after 24 min of incubation; numbers are the average from three
d
measurements. Blood glucose change (%) compared to vehicle at the 4 h time point after C57 mice were orally dosed with compound (50 mg/kg).
e
Lipophilic ligand efficiency (LLE) calculated as (pSC1.5 − clogP).
Information, indicated that the α-substituted phenylacetic acid
in 1 was the optimized fragment. Therefore, this moiety was
maintained, and our lead optimization was focused on the
aminopyrazine fragment. We envisioned that adding polar
groups to the 5-position of the 2-aminopyrazine in 1 could
reduce or eliminate the liabilities of CYP3A4 TDI and hERG
inhibition without sacrificing activator potency. To this end, a
series of 5-substituted-2-aminopyrazine-derived GK activators
were synthesized, and these compounds (4 and 9−24) were
assayed for their GK activation potency and their liability in
inactivating human CYP3A4 at a compound concentration of
10 μM. The effects of GK activators on the hERG potassium
channel were assessed using the patch clamp method, and dose-
dependent hERG inhibition was measured. Our goal was to
achieve a hERG IC20 value around 10 μM. Therefore, the
percentage of hERG inhibition at a compound concentration of
10 μM is listed in Table 1. Furthermore, these compounds were
evaluated for their ability to lower blood glucose in C57 mice in
comparison with vehicle dosing as listed in Table 1. As an
indication of improvement in the physicochemical properties of
these compounds, the lipophilic ligand efficiency (LLE) values
are also listed.14
As shown in Table 1, the 5-position of aminopyrazine-
derived GKAs can tolerate a large variety of functional groups.15
Except for 6, 9, and 14, all compounds achieved an
improvement in LLE, and 5 of them displayed an increase of
LLE greater than 1.0 when compared with 1 (13, 15, 16, 20,
and 4). It is also important to note that the diol stereochemistry
affected GK activation potency. The analogue with an (S)-
configuration exhibited four times higher potency than the
B
dx.doi.org/10.1021/ml400027y | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
corresponding (R)-configuration analogue (compare 4 with
24), which is significant in our assay. However, this chemical
series (except for 7) appears to possess a strong hERG
interaction pharmacophore and achieving a hERG IC20 value
less than 10 μM turned out to be challenging. Within the data
set in Table 1, only five diol-derived activators displayed hERG
inhibition about 20% at 10 μM (11, 12, 4, 22, and 24). In
general, carboxylic acids carry a lower hERG inhibition liability.
However, activators from aminopyridine- or aminopyrazine-
derived carboxylic acids in our phenylacetamide chemical series
did not demonstrate significant acute in vivo efficacy in
lowering blood glucose (data not shown). With regard to
CYP3A4 TDI, 8 compounds in Table 1 had a measured TDI
value less than 20% at the concentration of 10 μM.
Interestingly, replacing the methyl sulfide with the methyl
sulfoxide completely removed TDI of CYP3A4 (compare 9
with 10), while the two diol derivatives with alkoxy
substitutions (11 and 12) still showed TDI greater than 20%.
To study the acute glucose lowering efficacy of GK activators
in C57Bl/6J mice, animals (2 months old, n = 6 per dose group,
fasted for 2 h prior to oral dosing) were orally treated with 1, 4,
7, and 9−24 (50 mg/kg) or vehicle, and blood samples were
taken every two hours post dosing (2, 4, 6, and 8 h time
points). Changes in blood glucose levels compared to vehicle
treatment at the 4 h time point are listed in Table 1. Except for
7, all efficacy data in Table 1 achieved statistical significance (p
< 0.01 for 1, 4, 9−22, and 24; p = 0.038 for 23). As shown in
the list, 11 compounds achieved glucose lowering greater than
40%. The indicated hypoglycemic effects of these compounds
in C57 mice could be due to the relatively high dose.
Table 2. (A) Physicochemical and in vitro predictive safety
profiles of 4; (B) Pharmacokinetic properties of 4 in mouse
and dogs
A. properties
results
log D (pH = 7.4)
2.7
solubility (pH = 7.4)
pKa
0.17 mg/mL
11.42
caco-2 permeability (Papp)
human plasma protein binding (unbound Fu)
hERG IC50
3.36 × 10− 6cm/s
10%
70 μM
CYP (7 CYP isoforms) IC50
>30 μM
covalent binding to human liver microsomes (30 min, 33 pmol/mg
with NADPH)
protein
B. species
mouse
po
dog
route
iv
iv
10
8
po
30
dose (mg/kg)
Cl (mL/min/kg)
Vss (L/kg)
10
30
20.8
1.44
8,010
1.69
AUC0‑inf (ng hr/mL)
Cmax (ng/mL)
tmax (h)
12100
1310
4
21600
54500
3790
7.3
oral bioavailability (%)
50.3
84
By analyzing the data for hERG inhibition (20% @ 10 μM),
CYP3A4 TDI (<20% @ 10 μM), in vitro GK activation (SC1.5
< 0.50 μM), and in vivo acute glucose lowering (>30% @ 50
mg/kg) in Table 1, we concluded that both 4 and 22 satisfied
our criteria for compound selection. After investigation of
different crystallization methods, the crystalline form of
nonsolvated 4 was obtained. However, we did not obtain a
crystalline form of 22. Therefore, 4 was selected as a preclinical
lead molecule.
We next characterized the kinetic properties of GK at
different concentrations of 4. Enzymatic assays using
recombinant human GK indicated dose-dependent GK
activation by 4 at all glucose concentrations (Figure S1 in
Supporting Information). The enzyme kinetic profile of 4
demonstrated the ability of the compound to increase enzyme
Vmax from 10.0 μM/min to 16.0 μM/min (1.6 fold) and
decrease substrate SC0.5 (glucose concentration to reach half of
the Vmax) from 7.5 to 3.9 mM.
To further investigate 4 for its potential as an oral
antidiabetic agent, we studied 4 for drug-like properties. As
listed in Table 2A, 4 displayed good solubility and permeability,
with a hERG IC50 value greater than 50 μM. The desirable
physicochemical properties of 4 prompted us to investigate its
pharmacokinetic profiles in mice and dogs. As listed in Table
2B, good oral bioavailability was achieved in C57 mice and
dogs.
Encouraged by the pharmacokinetic profiles of 4, we further
assessed its dose-dependent efficacy on lowering glucose in
diet-induced obesity (DIO) mice. As shown in Figure 2, dose-
dependent lowering of blood glucose was observed after DIO
mice (n = 9 per dose, C57Bl/6J mice, 6 months old, on a high-
fat diet for 4 months) were orally treated with 4 (7.5, 15, and
30 mg/kg). At the time point of 2 and 4 h post oral dosing,
Figure 2. Compound 4 lowers basal glucose in DIO mice.
compound 4 (30 mg/kg) lowered basal glucose by 45% (p <
0.001). Even at the lower dose (15 mg/kg), compound 4 was
able to lower glucose levels at the 2 and 4 h time points by 32%
(p < 0.02), with an ED25 value of 10 mg/kg. A good correlation
of drug exposure level to blood glucose lowering was obtained
(Table S2 in Supporting Information).
The syntheses of 1, 7, 8, and the required left-hand piece 25
were carried out according to our earlier reported method.13
The starting material for compound 6 was prepared through
the nucleophilic substitution of 25 with sodium methoxide. The
synthetic schemes for the preparation of GKAs 9−21 and 23
including the intermediates are described in the Supporting
Information. The syntheses of 4 and 22 using the Sharpless
asymmetric dihydroxylation reaction16 are detailed in Scheme
1. The key step is the enantiomeric enrichment of the diol
through the crystallization of the corresponding acetonide 38.
This route allowed our medicinal chemistry lab to prepare a
large batch (200 g) of 4 for dose range finding studies.
To demonstrate that the issue of metabolite cycling was
resolved with 4, the 14C-labeled compound was incubated with
liver microsomes and hepatocytes from multiple species, and
the in vitro phase-1 metabolite pathway is described in Scheme
2. Unlike 2, which displayed significant ketone reduction in
human hepatocytes (35%, Table S3 in Supporting Information;
metabolism pathway for 2 has been reported13), 4 demon-
C
dx.doi.org/10.1021/ml400027y | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
a
a single oral dose of 100 mg in diabetic patients, which is
consistent with the metabolite cycling observed in metabolism
studies. However, the monohydroxylated forms 5a and 5b
exhibited significantly lower Cmax and exposure than the parent
4. The ketone, 5c, had the lowest exposure compared with the
parent and the monohydroxylated forms. The metabolite to
parent ratio for 2, [3]/[2], is 0.74 as calculated by Cmax and
1.39 as calculated by AUC. The corresponding ratios for 4 are
significantly lower (Table S6 in Supporting Information). The
low level of ketone 5c (4% of the parent by Cmax) suggests that
the potential for redox cycling has been significantly decreased.
In summary, we discovered a novel GK activator 4. This diol-
containing molecule showed improved lipophilic ligand
efficiency (LLE = 5.6) compared to the lead 1 (LLE = 4.0).
In the clinic, no evidence of metabolic cycling was seen in
contrast to observations from the previous clinical GKA, 2. The
lead optimization approach we took underscores the
importance of improving physicochemical properties in drug
design. The unique feature of the diol fragment to modulate
molecular properties paved the way for our further discovery of
potent and efficacious GKAs from other chemical scaffolds.17,18
Scheme 1. Syntheses of 22 and the Clinical Lead 4
a
Reagents and conditions: (a) Pd(PPh3)4 (cat), tributyl-(2-methyl-
propenyl)stannane, EtNPri2, LiCl, DMF, 130 °C; (b) compound 26,
pyridine, CH2Cl2; (c) K3Fe(CN)6, K2CO3, hydroquinine 1,4-
phthalazinediyl diether (cat), OsO4 (cat), t-BuOH/H2O, 0 °C, 18 h;
(d) pivaloyl chloride, pyridine, CH2Cl2; (e) potassium vinyltrifluor-
oborate, 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride,
ethanol, 100 °C; (f) 2,2-dimethoxypropane, p-toluene sulfonic acid
(cat), THF; (g) K2CO3, MeOH; (h) 2 N HCl (aq), THF.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed synthetic schemes for the synthesis of 9−21 and 23,
experimental procedures, preclinical data (Figure S1, Table S1−
S5), and clinical data (Figure S2 and Table S6). This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 2. In Vitro Phase-1 Metabolism Pathway of 4 in
Liver Microsomes and Hepatocytes
AUTHOR INFORMATION
Corresponding Author
*(Y.Q.) Tel: 973-235-3240. E-mail: yiminqian81@gmail.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Margret Jonca for chiral HPLC
analysis; Gino Sasso for 1H NMR characterization of
metabolites; Bruce Banner, Fred Bizzaro, Shaoqing Chen,
Steven Mischke, Lida Qi, and Kshitij Thakkar for chemistry
contributions; formulation, drug metabolism, and toxicology
groups for their support; Jefferson Tilley, Nader Fotouhi,
Joseph Grippo, and Rebecca Taub for project guidance; and
Karen Lackey for the management support of manuscript
preparation.
strated high stability (95%, Table S4 in Supporting
Information). A metabolism study of 4 with human liver
microsomes (Table S5 in Supporting Information) indicated
minimal formation of ketone 5c (M3) by further oxidation of
the alcohols 5a and 5b.
We previously reported compound 2 as the first GK activator
to reach the clinic. However, this molecule was stopped at the
phase 2 stage due to transient mild elevation of liver enzymes in
a very small percentage of patients. The mechanism for the
clinical observation remains unclear. One possibility is that
parent/metabolite cycling placed abnormal stress on the liver.
The successful resolution of metabolite cycling allowed us to
select 4 as a backup molecule to 2. Following thorough
preclinical safety assessment, 4 advanced to clinical testing in
type 2 diabetic patients.
REFERENCES
■
(1) Matschinsky, F. M. Assessing the potential of glucokinase
activators in diabetes therapy. Nat. Rev. Drug Discovery 2009, 8, 399−
416.
(2) Grimsby, J.; Sarabu, R.; Corbett, W. L.; Haynes, N. E.; Bizzarro,
F. T.; Coffey, J. W.; Guertin, K. R.; Hilliard, D. H.; Kester, R. F.;
Mahaney, P. E.; Marcus, L.; Qi, L.; Spence, C. L.; Tengi, J.; Magnuson,
M. A.; Chu, C. A.; Dvorozniak, M. T.; Matschinsky, F. M.; Grippo, J.
F. Allosteric activators of glucokinase: potential role in diabetes
therapy. Science 2003, 301, 370−373.
(3) Haynes, N. E.; Corbett, W. L.; Bizzarro, F. T.; Guertin, K. R.;
Hilliard, D. W.; Holland, G. W.; Kester, R. F.; Mahaney, P. E.; Qi, L.;
Spence, C. L.; Tengi, J.; Dvorozniak, M. T.; Railkar, A.; Matschinsky,
F. M.; Grippo, J. F.; Grimsby, J.; Sarabu, R. Discovery, structure−
activity relationships, pharmacokinetics, and efficacy of glucokinase
activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-
2-yl-propionamide (RO0281675). J. Med. Chem. 2010, 53, 3618−
3625.
The analysis of clinical data confirmed the significantly
different metabolite profile between 4 and 2 (Figure S2 in
Supporting Information). The parent ketone 2 and its
metabolite alcohol 3 showed comparable Cmax, with slightly
higher exposure for the metabolite 3 than the parent following
D
dx.doi.org/10.1021/ml400027y | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
(4) McKerrecher, D.; Allen, J. V.; Caulkett, P. W. R.; Donald, C. S.;
Fenwick, M. L.; Grange, E.; Johnson, K. M.; Johnstone, C.; Jones, C.
D.; Pike, K. G.; Rayner, J. W.; Walker, R. P. Design of a potent, soluble
glucokinase activator with excellent in vivo efficacy. Bioorg. Med. Chem.
Lett. 2006, 16, 2705−2709.
(5) (a) Waring, M. J.; Johnstone, C.; McKerrecher, D.; Pike, K. G.;
Robb, G. Matrix-based multiparameter optimization of glucokinase
activators: the discovery of AZD1092. Med. Chem. Commun. 2011, 2,
775−779. (b) Waring, M. J.; Clarke, D. S.; Fenwick, M. D.; Godfrey,
L.; Groombridge, S. D.; Johnstone, C.; McKerrecher, D.; Pike, K. G.;
Rayner, J. W.; Robb, G. R.; Wilson, I. Property based optimization of
glucokinase activators: discovery of phase IIb clinical candidate
AZD1656. Med. Chem. Commun. 2012, 3, 1077−1081.
(15) Chen, S.; Corbett, W. L.; Guertin, K. R.; Haynes, N.; Kester, R.
F.; Mennona, F. A.; Mischke, S. G.; Qian, Y.; Sarabu, R.; Scott, N. R.;
Thakkar, K. C. 5-Substituted-Six-Membered Heteroaromatic Glucokinase
Activators. U.S. Patent 7,132,425, 2006.
(16) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Catalytic
asymmetric dihydroxylation. Chem. Rev. 1994, 94, 2483−2547.
(17) Berthel, S. J.; Brinkman, J. A.; Hayden, S.; Haynes, N. E.; Kester,
R. F.; McDermott, L. A.; Qian, Y.; Sarabu, R.; Scott, N. R.; Tilley, J. W.
Pyrrolidinone Glucokinase Activators. U.S. Patent 7,741,327, 2010.
(18) Berthel, S. J.; Haynes, N. E.; Kester, R. F.; McDermott, L. A.;
Qian, Y.; Sarabu, R.; Scott, N. R.; Tilley, J. W. Pyridazinone Glucokinase
Activators. U.S. Patent 8,258,134, 2012.
(6) Mao, W.; Ning, M.; Liu, Z.; Zhu, Q.; Leng, Y.; Zhang, A. Design,
synthesis, and pharmacological evaluation of benzamide derivatives as
glucokinase activators. Bioorg. Med. Chem. 2012, 20, 2982−2991.
(7) Meininger, G. E.; Scott, R.; Alba, M.; Shentu, Y.; Luo, E.; Amin,
H.; Davies, M. J.; Kaufman, K. D.; Goldstein, B. J. Effects of MK-0941,
a novel glucokinase activator, on glycemic control in insulin-treated
patients with type 2 diabetes. Diabetes Care 2011, 34, 2560−2566.
(8) Takahashi, K.; Hashimoto, N.; Nakama, C.; Kamata, K.; Sasaki,
K.; Yoshimoto, R.; Ohyama, S.; Hosaka, H.; Maruki, H.; Nagata, Y.;
Eiki, J. I.; Nishimura, T. The design and optimization of a series of 2-
(pyridin-2-yl)-1H-benzimidazole compounds as allosteric glucokinase
activators. Bioorg. Med. Chem. 2009, 17, 7042−7051.
(9) Nishimura, T.; Iino, T.; Mitsuya, M.; Bamba, M.; Watanabe, H.;
Tsukahara, D.; Kamata, K.; Sasaki, K.; Ohyama, S.; Hosaka, H.;
Futamura, M.; Nagata, Y.; Eiki, J. I. Identification of novel and potent
2-amino benzamide derivatives as allosteric glucokinase activators.
Bioorg. Med. Chem. Lett. 2009, 19, 1357−1360.
(10) Bertram, L. S.; Black, D.; Briner, P. H.; Chatfield, R.; Cooke, A.;
Fyfe, M. C. T.; Murray, P. J.; Naud, F.; Nawano, M.; Procter, M. J.;
Rakipovski, G.; Rasamison, C. M.; Reynet, C.; Schofield, K. L.; Shah,
V. K.; Spindler, F.; Taylor, A.; Turton, R.; Williams, G. M.; Wong-Kai-
In, P.; Yasuda, K. SAR, pharmacokinetics, safety, and efficacy of
glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides:
discovery of PSN-GK1. J. Med. Chem. 2008, 51, 4340−4345.
(11) Bebernitz, G. R.; Beaulieu, V.; Dale, B. A.; Deacon, R.; Duttaroy,
A.; Gao, J.; Grondine, M. S.; Gupta, R. C.; Kakmak, M.; Kavana, M.;
Kirman, L. C.; Liang, J.; Maniara, W. M.; Munshi, S.; Nadkarni, S. S.;
Schuster, H. F.; Stams, T.; St. Denny, I.; Taslimi, P. M.; Vash, B.;
Caplan, S. L. Investigation of functionally liver selective glucokinase
activators for the treatment of type 2 diabetes. J. Med. Chem. 2009, 52,
6142−6152.
(12) Pfefferkorn, J. A.; Guzman-Perez, A.; Litchfield, J.; Aiello, R.;
Treadway, J. L.; Pettersen, J.; Minich, M. L.; Filipski, K. J.; Jones, C. S.;
Tu, M.; Aspnes, G.; Risley, H.; Bian, J.; Stevens, B. D.; Bourassa, P.;
D’Aquila, T.; Baker, L.; Barucci, N.; Robertson, A. S.; Bourbonais, F.;
Derksen, D. R.; MacDougall, M.; Cabrera, O.; Chen, J.; Lapworth, A.
L.; Landro, J. A.; Zavadoski, W. J.; Atkinson, K.; Haddish-Berhane, N.;
Tan, B.; Yao, L.; Kosa, R. E.; Varma, M. V.; Feng, B.; Duignan, D. B.;
El-Kattan, A.; Murdande, S.; Liu, S.; Ammirati, M.; Knafels, J.; DaSilva-
Jardine, P.; Sweet, L.; Liras, S.; Rolph, T. P. Discovery of (S)-6-(3-
cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)-
nicotinic acid as a hepatoselective glucokinase activator clinical
candidate for treating type 2 diabetes mellitus. J. Med. Chem. 2012,
55, 1318−1333.
(13) Sarabu, R.; Bizzarro, F. T.; Corbett, W. L.; Dvorozniak, M. T.;
Geng, W.; Grippo, J. F.; Haynes, N. E.; Hutchings, S.; Garofalo, L.;
Guertin, K. R.; Hilliard, D. W.; Kabat, M.; Kester, R. F.; Wang, K.;
Liang, Z.; Mahaney, P. E.; Marcus, L.; Matschinsky, F. M.; Moore, D.;
Racha, J.; Radinov, R.; Ren, Y.; Qi, L.; Pignatello, M.; Spence, C. L.;
Steele, T.; Tengi, J.; Grimsby, J. Discovery of Piragliatin-first
glucokinase activator studied in type 2 diabetic patients. J. Med.
Chem. 2012, 55, 7021−7036.
(14) Meanwell, N. A. Improving drug candidates by design: a focus
on physicochemical properties as a means of improving compound
disposition and safety. Chem. Res. Toxicol. 2011, 24, 1420−1456.
E
dx.doi.org/10.1021/ml400027y | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX