23 research outputs found
Discovery of AZD2716: A Novel Secreted Phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) Inhibitor for the Treatment of Coronary Artery Disease
Expedited
structure-based optimization of the initial fragment hit <b>1</b> led to the design of (<i>R</i>)-<b>7</b> (AZD2716)
a novel, potent secreted phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) inhibitor with excellent preclinical pharmacokinetic properties
across species, clear <i>in vivo</i> efficacy, and minimized
safety risk. Based on accumulated profiling data, (<i>R</i>)-<b>7</b> was selected as a clinical candidate for the treatment
of coronary artery disease
Selective and Bioavailable HDAC6 2â(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism
Histone deacetylase 6 (HDAC6) is a unique member of the
HDAC family
mainly targeting cytosolic nonÂhistone substrates, such as α-tubulin,
cortactin, and heat shock protein 90 to regulate cell proliferation,
metastasis, invasion, and mitosis in tumors. We describe the identification
and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles
(DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing
structureâactivity relationships and performing quantum mechanical
calculations of the HDAC6 catalytic mechanism, we show that potent
oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism
for the bioactivation. We also observe that the inherent electrophilicity
of the oxadiazoles makes them prone to degradation in water solution
and the generation of potentially toxic products cannot be ruled out,
limiting the developability for chronic diseases. However, the oxadiazoles
demonstrate high oral bioavailability and low in vivo clearance and
are excellent tools for studying the role of HDAC6 in vitro and in
vivo in rats and mice
Selective and Bioavailable HDAC6 2â(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism
Histone deacetylase 6 (HDAC6) is a unique member of the
HDAC family
mainly targeting cytosolic nonÂhistone substrates, such as α-tubulin,
cortactin, and heat shock protein 90 to regulate cell proliferation,
metastasis, invasion, and mitosis in tumors. We describe the identification
and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles
(DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing
structureâactivity relationships and performing quantum mechanical
calculations of the HDAC6 catalytic mechanism, we show that potent
oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism
for the bioactivation. We also observe that the inherent electrophilicity
of the oxadiazoles makes them prone to degradation in water solution
and the generation of potentially toxic products cannot be ruled out,
limiting the developability for chronic diseases. However, the oxadiazoles
demonstrate high oral bioavailability and low in vivo clearance and
are excellent tools for studying the role of HDAC6 in vitro and in
vivo in rats and mice
Selective and Bioavailable HDAC6 2â(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism
Histone deacetylase 6 (HDAC6) is a unique member of the
HDAC family
mainly targeting cytosolic nonÂhistone substrates, such as α-tubulin,
cortactin, and heat shock protein 90 to regulate cell proliferation,
metastasis, invasion, and mitosis in tumors. We describe the identification
and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles
(DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing
structureâactivity relationships and performing quantum mechanical
calculations of the HDAC6 catalytic mechanism, we show that potent
oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism
for the bioactivation. We also observe that the inherent electrophilicity
of the oxadiazoles makes them prone to degradation in water solution
and the generation of potentially toxic products cannot be ruled out,
limiting the developability for chronic diseases. However, the oxadiazoles
demonstrate high oral bioavailability and low in vivo clearance and
are excellent tools for studying the role of HDAC6 in vitro and in
vivo in rats and mice
Selective and Bioavailable HDAC6 2â(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism
Histone deacetylase 6 (HDAC6) is a unique member of the
HDAC family
mainly targeting cytosolic nonÂhistone substrates, such as α-tubulin,
cortactin, and heat shock protein 90 to regulate cell proliferation,
metastasis, invasion, and mitosis in tumors. We describe the identification
and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles
(DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing
structureâactivity relationships and performing quantum mechanical
calculations of the HDAC6 catalytic mechanism, we show that potent
oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism
for the bioactivation. We also observe that the inherent electrophilicity
of the oxadiazoles makes them prone to degradation in water solution
and the generation of potentially toxic products cannot be ruled out,
limiting the developability for chronic diseases. However, the oxadiazoles
demonstrate high oral bioavailability and low in vivo clearance and
are excellent tools for studying the role of HDAC6 in vitro and in
vivo in rats and mice
X-ray crystallography.
<p>Data collection and refinement statistics.</p><p><sup>1</sup>Values in parentheses refer to highest-resolution shell.</p><p>X-ray crystallography.</p
Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design
<div><p>Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1â-S2â FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1â-S2â binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC<sub>50</sub> of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1â-S2â binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.</p></div
Synthesis of P1â-P2â fragments.
<p>i) DCM, r.t, 16h, then LiOH, water, THF, r.t, 16h, then PPA, 120°C, 2h, ii) TBTU, DIPEA, DMF, L-phenylalanine methylester, r.t, 16h, iii) TBTU, pyridine, MeNH2xHCl, DMF, r.t, 16h, iv) TBTU, (S)-2-amino-N,N-dimethyl-3-phenylpropanamide hydrochloride, TEA, DMF, r.t, 16h, v) TBTU, TEA, DCM, DMF, r.t, 16h, vi) neat TFA, r.t, 0.5h.</p
Synthesis of 3-substituted quinolinone 23.
<p>i) Piperidine, EtOH, reflux, 6h, ii) DIBAL-H, Et2O, N2, r.t, iii) Neat SOCl2, reflux, 6h, iv) DEM, NaH, THF, N2, reflux, 2h, v) Conc. HCl, reflux, 16h, vi) 20B, TBTU, DIPEA, DMF, r.t, 16h.</p
Crystal structures of compounds 9, 12 and 13 in complex with FXIa.
<p>Compounds 9 (green), 12 (magenta) and compound 13 (yellow) are overlaid. The protein surface from the FXIa CD:compound 9 complex is shown as grey surface and the central water molecule that interacts with both amides is shown as sphere.</p