WO2011053597A1 - Inhibiteurs d'autotaxine dérivés d'acide pipémidique - Google Patents

Inhibiteurs d'autotaxine dérivés d'acide pipémidique Download PDF

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WO2011053597A1
WO2011053597A1 PCT/US2010/054143 US2010054143W WO2011053597A1 WO 2011053597 A1 WO2011053597 A1 WO 2011053597A1 US 2010054143 W US2010054143 W US 2010054143W WO 2011053597 A1 WO2011053597 A1 WO 2011053597A1
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atx
compounds
mmol
autotaxin
compound
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Abby Louise Parrill-Baker
Daniel Lee Baker
Adrienne Hoeglund
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The University Of Memphis Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Definitions

  • Novel and optimized classes of pipemidic acid derivative compounds that exhibit effective inhibition of autotaxin enzymes are provided.
  • Such classes of compounds exhibit reactivity with autotaxin to ultimately reduce the size of the reactive sites thereon to prevent conversion of lysophosphatidyl choline to lysophophatidic acid.
  • such compounds can be incorporated within delivery forms for human ingestion. As such, these compounds accord an excellent manner of potentially reducing generation of certain cancers attributable to the presence of naturally occurring autotaxin within the human body. Methods of inactivating autotaxin to certain degrees therewith such compounds are encompassed within invention as well.
  • pyrophosphatase phosphodiesterase 2 is an enzyme secreted within the human body.
  • This molecule has been known for generating (LP A) through conversion of lysophosphatidyl-choline (LPC) thereto via lysophospholipase D activity (the removal of choline from the base compound generates LP A).
  • LP A has been realized to contribute to tumor cell growth, unfortunately, as the reactivity within the human body of LPA within certain tissues has resulted, in certain studies, in cancerous growths when present at certain levels. In this manner, then, it has been theorized that the greater the incidence of autotaxin activity within the human body, the greater the possibility of LPA generation.
  • a reduction in the catalytic capabilities of autotaxin to convert the LPC molecule to LPA would theoretically permit an ultimate reduction in possibility of unwanted cell proliferation through reduced LPA presence within a subject's body.
  • LPA The mechanism of autotaxin in terms of enzymatic activity and catalysis to form LPA resides in its phosphodiesterase capability.
  • LPA can be generated from the cleavage of the phosphodiester bonds of LPC, through the function of a phospholipase enzyme (note Formula I).
  • this enzymatic catalysis of LPC removes the choline group, leaving LPA, which has a tendency to stimulate cell growth and proliferation as well as chemotaxis. From this, it appears that the motility of tumor cells is increased as well, resulting in properties and gene expression within certain carcinomas (such as, for instance, breast cancer cells), causing further processing into a form that is bioactive and potentially dangerous. Metastasis and oncogenesis of cancer cells appear to occur as well with elevated levels of LPA present within a targeted region.
  • Increased ATX expression has been identified in renal carcinoma, metastatic breast cancer, thyroid carcinoma, Hodgkin lymphoma, and invasive glioblastoma multiforme, as well as other diseases, including multiple sclerosis, obesity, diabetes, Alzheimer's diseases, and chronic pain. It has thus been determined that the ability to prevent, or at least reduce, the amount of LPA within the human body holds great promise at, likewise, reducing, if not preventing, the onset of certain diseases, most prominently, certain cancers. It has been theorized, as noted above, that autotaxin modifications may prevent the undesirable conversion from LPC to LPA; the ability to actually accomplish such a result has been elusive, however, at least to the degree necessary for effective broad-scale utilization of such a method. Any modification thereof must exhibit an ability to drastically reduce the activity of autotaxin while also, preferably exhibiting oral bioavailability as well.
  • ATX Autotaxin
  • NPP2 lysophospholipase D enzyme responsible for synthesis of the bioactive lipid lysophosphatidic acid (LPA) in vivo.
  • LPA bioactive lipid lysophosphatidic acid
  • metal chelators examples include metal chelators, lipid analogs and non-lipid, small molecules have all been identified as autotaxin inhibitors.
  • Metal chelators such as EDTA, phenanthroline, and L- histidine have been shown to inhibit ATX activity, presumably via interactions with active site divalent metal ions required for function.
  • Lipid analogs represent the largest group of reported ATX inhibitors (see Figure 1 for structures).
  • LPA and the related bioactive lipid sphingosine 1- phosphate (SIP) were previously shown to function as feedback inhibitors of ATX. This discovery led to the analysis of several LPA and SIP analogs as ATX inhibitors.
  • Reported LPA analogs include fatty alcohol phosphates, Darmstoff analogs, cyclic phosphatidic acid analogs, and phosphonates (VPC8a202, S32826, and JGW-8).
  • S IP analog FTY720- phosphate
  • R' aromatic, heteroaromatic, cyclohexyl
  • ATX inhibitors consists of non-lipid, small molecules that collectively extend structural diversity and in general possess physicochemical characteristics more closely related to orally bioavailable drugs.
  • group Figure A The most efficacious structures previously identified are shown in group Figure A, below.
  • H2L 7905958 (1) was the most efficacious compound from that initial single concentration screen (at 10 ⁇ compound 1 fully inhibited ATX-catalyzed hydrolysis of 1 ⁇ FS-3).
  • additional small-molecule inhibitors of ATX (group Figures B and C) were identified as potential as metastasis blockers as well.
  • NSC 48300 in group Figure C, showed essentially 100% inhibition of melanoma metastasis at micromolar concentrations. Although this compound, and the group of compounds similar thereto, exhibited acceptable, if not effective autotaxin inhibition, it is not clear if such compounds are selective to ATX (NPP2).
  • LP A and SIP suggests that product feedback inhibition may contribute to regulation of ATX function in vivo.
  • Additional reported ATX inhibitors share several common structural features, including a phosphate, thiophosphate, or phosphonate headgroup attached either with or without a linker to an alkyl chain, which can vary in overall length and can be either saturated or
  • ATX is a member of the nucleotide pyrophosphatase/phosphodiesterase (NPP) family, as well as the alkaline phosphatase superfamily. Crystallographic structures of several alkaline phosphatase superfamily members have been available for decades. These crystal structures show remarkable structural conservation in a small core surrounding the catalytic site, but unfortunately show completely different structural characteristics outside this conserved core.
  • NPP nucleotide pyrophosphatase/phosphodiesterase
  • Sequence homology of the alkaline phosphatases with ATX does not exceed 14% and is therefore insufficient for generation of a high quality homology model in any region outside the approximately 100 amino acid structurally conserved core.
  • the recent report of a crystal structure of a bacterial NPP enzyme with 30% identity to the ATX catalytic core domain enabled the development of a structural model of the ATX catalytic domain that may prove useful in structure-based drug design.
  • a significant improvement such a homology model must be applied cautiously as involvement of the c-terminal nuclease-like domain in substrate recognition has been suggested from studies of NPP family domain-swapping chimeras.
  • these previously reported ATX inhibitors are analogs of LPA, a phospholipid, and are more hydrophobic than is typical of orally bioavailable drugs, thereby creating problems in that area.
  • NPP6 and NPP7 are examples of NPP-type compounds
  • the determination of proper selective NPP2 inhibiting compounds can thus aid in not only further optimization of autotaxin treatment agents, but also an understanding of the actual amino acid structures outside of the ATX conservative core.
  • some compounds may promote ATX inhibition as they currently exist, some others with homologous structures (at least to a certain degree) to such effective ATX reduction agents may serve as intermediate compounds for further reaction and/or modification for such an optimization process.
  • previous attempts at such treatments have provided developments of certain classes of compounds that exhibit certain desired results with ATX inhibition.
  • the generation of classes that effectively provide increased overall ATX inhibition characteristics has been lacking in the pharmaceutical industry.
  • the present invention provides not only improved ATX inhibiting compounds, but possible intermediates as launching pads into further improvement possibilities within this area as well.
  • this invention encompasses a method for reducing autotaxin activity to modify LPC to LPA, said method involving the reaction of autotaxin with at least one pipemidic acid derivative compound.
  • a treatment method would involve a reaction product of pipemidic acid and a phenylthiourea compound. More specifically, the reaction product would exhibit, preferably, though not necessarily, at least one pendant group on the ring of the phenylthiourea reactant in the meta- position to the thiourea linking group to the pipemidic acid constituent.
  • R Rs may be selected individually from the group consisting of hydrogen, halogen, Q-C 1 alkyl, Ci-C] 8 alkoxy, Cj-Cig alkenyl, Ci-Cj 8 carboxyl, Ci-Ci 8 carboxyalkyl, C Cis alkoxy, Ci-C 18 halogen-substituted alkyl, any two of such groups forms a cycloalkyl ring, any two of such groups forms an heterocyclic ring (such as including a nitrogen atom therein), with, at least one group being something other than hydrogen (and others as presented below on page 14).
  • R ls R 3 , and R 5 are hydrogen, and R 2 and R4 being any other group as noted. Most preferably only one of R 2 and R4 is any such group other than hydrogen as well, and still more preferably wherein such a group is a halogen or a trihaloalkyl group:
  • This inventive method thus concerns the treatment, via any available manner, such as intravenous, oral ingestion, and the like, of a mammalian subject to reduce autotaxin availability therein.
  • Such an inventive method may also encompass the broad treatment of the same subject for a number of different maladies associated with autotaxin presence and activity within the subject's body (such as to treat obesity, atherosclerosis, and the like, as noted herein), rather than simply for cancer treatments alone.
  • the specific compounds that exhibit greater than 50% response at a single 10 ⁇ dose and/or a K t of less than 2 ⁇ for ATX inhibition are within the scope of this invention.
  • Figure 1 is a graphical representation of the autotaxin inhibition capability of lead compound A, as depicted below.
  • Figure 2 is a graphical representation of the reactivity of lead compound A, as depicted below, in terms of Ki measurements.
  • Figure 3 is a histogram representation of autotaxin inhibition of representative inventive compounds.
  • Figure 4 is a graphical represntation of autotaxin inhibition rates for representative inventive compounds.
  • Figure 5 is a histogram representation of cell migration characteristics related to certain representation inventive compounds.
  • Pipemidic acid itself has been used in the past as an antibacterial compound (quinolone- type antibiotics have been widely used for nearly a century, in fact). Derivatives of such a base compound have been developed as improved antibiotics as well through the years. However, such compounds have involved the modification of the actual pipemidic acid backbone (such as replacing an aza group from an heterocyclic constituent with a methylfiuoro substituent, or replacing the N-ethyl group with a N-cyclopropyl moiety, as examples) rather than reacting the pipemidic acid with an additive group and retaining the pipemidic acid backbone in total (save for the reactive hydrogen attached to the heterocyclic nitrogen).
  • inventive compounds were in essence developed through the realization that a first small molecule ATX inhibitor, noted below as lead compound A exhibited high efficacy as an autotaxin inhibitor. As noted, such a compound exhibited effective response to autotaxin activity (Graph B)( Figure 1) as well as AT, at micromolar concentrations (Graph C)( Figure 2).
  • Inhibitors with reported mechanism of inhibition include L- histidine, LPA and S IP, FTY720-phosphate, and non-lipid small molecules.
  • L-histidine demonstrates non-competitive inhibition.
  • LPA and S IP demonstrated mixed-mode inhibition with LPA having a K ⁇ of -0.1 ⁇ , and it was reported that FTY720-phosphate inhibited ATX in the low millimolar range by a competitive mechanism with a K ⁇ of 0.2 ⁇ .
  • certain non-lipid, small molecules such as NSC 48300 (as provided structurally on page 6, above) demonstrated potency in nanomolar concentrations as competitive ATX inhibitors.
  • NPP2 Three members of the NPP enzyme family, NPP2 (ATX), NPP6 and NPP7, share the ability to hydrolyze lysophospholipids, and therefore might be expected to have some overlap in their recognition of inhibitors.
  • autotaxin is the primary source for LPC conversion to the targeted LPA culprit, the ability to concentrate the effectiveness of an ATX inhibitor on that structure alone (without the appreciable potential for wasted amounts of inhibitor being used up in inhibiting other NPP-type enzymes) is a significant, albeit, as noted, unexamined possibility.
  • inventive pipemidic acid derivative compounds unexpectedly exhibit such a phenomenon of selectivity for ATX among the NPP isoforms with demonstrated preference for phospholipid substrates.
  • compositions be orally ingestable, but they may, as noted above, be provided for intravenous introduction as well.
  • compositions may take, any orally ingestable form is possible. This list includes, without limitation, liquids, liquid capsules, tablets, coated tablets, minitablets, capsules with individual beads, and the like. If in coated tablet form, such compositions may be of sustained release type, and may include a water insoluble but permeable film coating surrounding a core tablet and a particulate, water-soluble, pore-forming material dispersed within the film coating. Such a system thus provides an osmotic gradient and channel forming system. Typical coatings have included carnauba wax, cysteine hydrochloride, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. Other therapeutic agents may be included with these anticancer (autotaxin inhibiting) agents as well, as long as neither interferes with the effectiveness of the other in the user's body.
  • anticancer autotaxin inhibiting
  • this invention is directed to a novel method of treating patients with suitable ATX inhibiting compounds.
  • Such compounds were determined through a very efficient screening procedure, and exist as lead compounds with the potential to treat metastasis, obesity, neuropathic pain, atherosclerosis and rheumatoid arthritis, at least, within a mammalian body.
  • the autotaxin (ATX) enzyme promotes cell migration and invasion, thus inhibition of ATX is of value for prevention of metastasis and the other maladies noted previously.
  • assays were prepared for comparative reactivity measurements with other NPP isoforms (NPP6 and NPP7)(ATX is NPP2, as noted previously). Such methods were conducted as follows:
  • ATX inhibition was assayed using the substrate FS-3 (Echelon Biosciences, Inc., Salt Lake City, UT, USA).
  • the FS-3 assay used ⁇ 10 times concentrated conditioned serum-free medium (CCM) from MDA-MB-435 cells as the source of ATX, while CCM comprised one- third of the total volume.
  • the final volume for FS-3 was comprised of the substrate at varying concentrations and 30 ⁇ charcoal-stripped fatty acid free BSA (Sigma Aldrich) in assay buffer (1 mM each CaCl 2 and MgCl 2 , 5 mM KC1, 140 mM NaCl, 50 mM Tris pH 8.0).
  • ATX kinetics assays were performed using eight different concentrations of substrate and two different concentrations of inhibitor (ChemBridge, San Diego, CA).
  • the FS-3 substrate concentrations ranged from 20 - 0.3 ⁇ on the plate.
  • the normalized fluorescence results were plotted as a function of time in order to determine initial rates.
  • the initial rates were plotted against the substrate concentration and a rectangular hyperbolic curve was fitted to the data using the KaleidaGraph software (Synergy Software, Reading, PA, Version 4.03).
  • the K m and V max were calculated from the resulting plots.
  • Mode of inhibition was determined from the inhibitor effect on K m and V max values.
  • the dissociation constant (Kj) for inhibitor binding was calculated for each of the inhibitors.
  • Kj for uncompetitive inhibition was calculated using Equation 1 (Cheng and Prusoff, 1973). Equation 2 was used for competitive inhibition (Cheng and Prusoff, 1973).
  • MDA-MB-435 cells were cultured at 37°C under a humidified atmosphere containing 5% C0 2 in Dulbecco's Modified Eagle Medium (DMEM) (MediaTech, Herndon, VA) containing 100 U/ml penicillin, 100 ⁇ g/ml streptomycin (Hyclone, Logan, UT), 5% fetal bovine serum (FBS) (Hyclone, Logan, UT), and 2 mM L-glutamine (Hyclone, Logan, UT). Upon reaching 80 to 95% confluency, the cells were washed twice with sterile phosphate buffered saline. Serum- free DMEM containing L-glutamine and antibiotics was then added to the cells.
  • DMEM Dulbecco's Modified Eagle Medium
  • Conditioned media was collected after 36-48 hours of incubation with serum-free DMEM.
  • the media was concentrated ⁇ 10X and buffer exchanged into Tris (50 mM, pH 7.4) containing 20% ethylene glycol using 30 kDa molecular weight cutoff filters (Millipore, Beverly, MA) in an Amico pressure cell (Millipore, Beverly, MA). Aliquots of 10X conditioned media were stored at 4 ° C.
  • Inhibitor selectivity was assayed using -nitrophenylphosphoryl-choline (pNPPC) (Sigma-Aldrich, St. Louis, MO) as substrate for NPP6 and NPP7.
  • the final volume 60 ⁇ , included 20 ih (CM, NPP6 or CCM, NPP7, 20 ⁇ L inhibitor (10 ⁇ including l%DMSO) in assay buffer, and 20 pNPPC (10 mM, NPP6 or 1 ⁇ , NPP7) in assay buffer.
  • NPP6 assay buffer contained 500mM NaCl, 0.05% Triton X-100, l OOmM Tris-HCl (pH 9.0), whereas NPP7 assay buffer was comprised of 50mM Tris HC1, pH 8.5, 150 mM NaCl, and 10 mM taurocholic acid. However, unlike the published methods, EDTA was not added to the NPP7 assay buffer. All assays were performed in 96-well, half area plates (Corning Inc., Lowell, MA) at 37 ° C with data collected at 2 minute intervals using a Synergy2 absorbance plate reader (BioTek, Winooski, VT).
  • Results are shown at the one hour time point, when all absorbance changes as a function of time were linear. Readings were normalized to vehicle control after subtraction of absorbance in the absence of CM or CCM. Data are shown as the mean ⁇ S.D. of at least three wells. All experiments were repeated twice and representative results are shown.
  • CM or CCM from HEK293 cells transiently transfected with NPP6 and 7 expression plasmids, respectively.
  • HEK293 cells were seeded in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum, 100 U/ml penicillin, 100 g/ml streptomycin (Hyclone, Logan, UT), and 2mM L-glutamine.
  • DMEM Dulbecco's modified Eagle's medium
  • HEK293 cells were grown overnight at 37°C under 5% C0 2 to 80% confluence.
  • the cells were then transfected with human NPP6ex 51 or human NPP7ex expression plasmids in the pcDNA3.1 (+) mammalian vector in the presence of Polyfect Transfection Reagent (Hyclone, Logan, UT). Six hours after transfection, the culture medium was changed to serum free DMEM containing L-glutamine and cells were incubated for 48 hours. Expressed protein was collected (NPP6 and NPP7) and concentrated ⁇ 10X (NPP7) using 10 kDa molecular weight cutoff filters (Millipore, Beverly, MA) in an Amicon pressure cell (Millipore, Beverly, MA).
  • Table 1 shows the results of SAR elaboration and optimization of lead compound H2L7905958 (1). Compounds showing improved K values over the lead are emphasized in bold italic font. Values shown in parentheses refer to the compound numbers ( Figure 5). Errors where indicated are standard deviations of at least three independent experiments. IC 50 values lacking standard deviations are averages of two independent experiments that were less than 3% different in value. TABLE 1
  • Table 2 summarizes two important trends that we observed with these analogs, being single dose response comparison by aromatic substituent and position. Values shown in parentheses refer to the compound numbers as in Table 1.
  • A2058 cells were seeded in 96- well plates at a density of 50,000 cells per well in complete growth medium (DMEM + 10% FBS + penicillin/streptomycin + L-glutamine). Cells were allowed to equilibrate for 24 hours at 37°C with 5% C0 2 . Cells were then serum-deprived for 24 hours in DMEM + 0.1 % BSA + penicillin/streptomycin + L-glutamine (serum- free medium). After 24 hours, the monolayer was scratched using a sterile 200 ⁇ pipette tip, and each well was washed with 50 ⁇ serum-free medium to remove damaged cells and treated with
  • LPA 18 1 (10 ⁇ ), LPC 18: 1 (10 ⁇ ), ATX (100 ng/ml), or a combination of LPC 18: 1 and
  • Compound 1 shows statistically significant inhibition of cell migration stimulated by ATX/LPC co-treatment. This data demonstrate that the in vitro enzyme inhibition observed for this compound translates into a cellular assay system relevant to metastasis.

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Abstract

L'invention porte sur de nouvelles classes optimisées de composés dérivés d'acide pipémidique qui présentent une inhibition efficace d'enzymes d'autotaxine. De telles classes de composés présentent une réactivité avec l'autotaxine pour réduire finalement la taille des sites réactifs sur celle-ci afin d'empêcher la conversion de lysophosphatide choline en acide lysophosphatidique. De plus, ces composés peuvent être incorporés dans des formules posologiques pour une administration aux humains. Ainsi, ces composés procurent une manière excellente de réduction potentielle de génération de certains cancers attribuables à la présence d'autotaxine se produisant naturellement à l'intérieur du corps humain. L'invention porte également sur des procédés de désactivation d'autotaxine à certains degrés avec celle-ci de telle sorte que les composés sont compris à l'intérieur de l'invention.
PCT/US2010/054143 2009-10-26 2010-10-26 Inhibiteurs d'autotaxine dérivés d'acide pipémidique WO2011053597A1 (fr)

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Cited By (11)

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WO2013142628A2 (fr) * 2012-03-20 2013-09-26 Fred Hutchinson Cancer Research Center Composés et compositions antibiotiques, et procédés d'identification associés
WO2014133112A1 (fr) * 2013-03-01 2014-09-04 国立大学法人東京大学 Dérivé imidazopyrimidinone substitué en position 8 présentant une activité inhibitrice de l'autotaxine
US9051320B1 (en) 2014-08-18 2015-06-09 Pharmakea, Inc. Methods for the treatment of metabolic disorders by a selective small molecule autotaxin inhibitor
US9334261B2 (en) 2013-11-22 2016-05-10 Pharmakea, Inc. Autotaxin inhibitor compounds
US9714240B2 (en) 2013-09-17 2017-07-25 Pharmakea, Inc. Vinyl autotaxin inhibitor compounds
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US9926318B2 (en) 2013-11-22 2018-03-27 Pharmakea, Inc. Tetracyclic autotaxin inhibitors
US9951026B2 (en) 2013-09-17 2018-04-24 Pharmakea, Inc. Heterocyclic vinyl autotaxin inhibitor compounds
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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013142628A3 (fr) * 2012-03-20 2013-12-05 Fred Hutchinson Cancer Research Center Composés et compositions antibiotiques, et procédés d'identification associés
WO2013142628A2 (fr) * 2012-03-20 2013-09-26 Fred Hutchinson Cancer Research Center Composés et compositions antibiotiques, et procédés d'identification associés
WO2014133112A1 (fr) * 2013-03-01 2014-09-04 国立大学法人東京大学 Dérivé imidazopyrimidinone substitué en position 8 présentant une activité inhibitrice de l'autotaxine
US9714240B2 (en) 2013-09-17 2017-07-25 Pharmakea, Inc. Vinyl autotaxin inhibitor compounds
US9951026B2 (en) 2013-09-17 2018-04-24 Pharmakea, Inc. Heterocyclic vinyl autotaxin inhibitor compounds
US9850203B2 (en) 2013-09-26 2017-12-26 Pharmakea, Inc. Autotaxin inhibitor compounds
US9926318B2 (en) 2013-11-22 2018-03-27 Pharmakea, Inc. Tetracyclic autotaxin inhibitors
US9468628B2 (en) 2013-11-22 2016-10-18 Pharmakea, Inc Autotaxin inhibitor compounds
US9334261B2 (en) 2013-11-22 2016-05-10 Pharmakea, Inc. Autotaxin inhibitor compounds
US9999615B2 (en) 2013-11-22 2018-06-19 Pharmakea, Inc. Autotaxin inhibitor compounds
US10688081B2 (en) 2013-11-22 2020-06-23 Sabre Therapeutics Llc Autotaxin inhibitor compounds
US11344533B2 (en) 2013-11-22 2022-05-31 Sabre Therapeutics Llc Autotaxin inhibitor compounds
US11779568B2 (en) 2013-11-22 2023-10-10 Sabre Therapeutics Llc Autotaxin inhibitor compounds
US9051320B1 (en) 2014-08-18 2015-06-09 Pharmakea, Inc. Methods for the treatment of metabolic disorders by a selective small molecule autotaxin inhibitor
US10138230B2 (en) 2015-02-04 2018-11-27 Cancer Research Technology Limited Autotaxin inhibitors
US10428061B2 (en) 2015-02-04 2019-10-01 Cancer Research Technology Limited Autotaxin inhibitors
US10654846B2 (en) 2015-02-06 2020-05-19 Cancer Research Technology Limited Autotaxin inhibitory compounds
US11453666B2 (en) 2015-02-06 2022-09-27 Cancer Research Technology Limited Autotaxin inhibitory compounds
US10632104B2 (en) 2015-05-27 2020-04-28 Sabre Therapeutics Llc Autotaxin inhibitors and uses thereof

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