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ACS Medicinal Chemistry Letters
ACS Med Chem Lett. 2017 Jun 8; 8(6): 608–613.
Published online 2017 May 3. doi:10.1021/acsmedchemlett.7b00103
PMCID: PMC5467183
PMID: 28626519
Xiaojing Wang,
*† James Barbosa,‡ Peter Blomgren,‡ Meire C. Bremer,† Jacob Chen,† James J. Crawford,† Wei Deng,§ Liming Dong,§ Charles Eigenbrot,† Steve Gallion,‡ Jonathon Hau,† Huiyong Hu,† Adam R. Johnson,† Arna Katewa,† Jeffrey E. Kropf,‡ Seung H. Lee,‡ Lichuan Liu,† Joseph W. Lubach,† Jen Macaluso,‡ Pat Maciejewski,‡ Scott A. Mitchell,‡ Daniel F. Ortwine,† Julie DiPaolo,‡ Karin Reif,† Heleen Scheerens,† Aaron Schmitt,‡ Harvey Wong,† Jin-Ming Xiong,‡ Jianjun Xu,‡ Zhongdong Zhao,‡ Fusheng Zhou,§ Kevin S. Currie,‡ and Wendy B. Young*†
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Associated Data
- Supplementary Materials
Abstract
In our continued effort to discoverand develop best-in-class Bruton’s tyrosine kinase (Btk) inhibitorsfor the treatment of B-cell lymphomas, rheumatoid arthritis, and systemiclupus erythematosus, we devised a series of novel tricyclic compoundsthat improved upon the druglike properties of our previous chemicalmatter. Compounds exemplified by G-744 are highly potent,selective for Btk, metabolically stable, well tolerated, and efficaciousin an animal model of arthritis.
Keywords: Kinase inhibitor, Btk, Rheumatoidarthritis, Lupus, G-744
Bruton’styrosine kinase (Btk) plays a critical role in the function of B cellsand myeloid cells, making it an attractive target for the treatmentof immunological disorders such as rheumatoid arthritis (RA), systemiclupus erythematosus (SLE), multiple sclerosis (MS)1−4 as well as B-cell lymphomas.5 Accordingly, there have been significant effortsfrom the pharmaceutical community toward identifying Btk inhibitorsfor clinical evaluation.6−14 Of these, the most advanced compound to date is ibrutinib, recentlyapproved for treatment of Mantle Cell Lymphoma (MCL), chronic lymphocyticleukemia (CLL), and Waldenstrom’s macroglobulinemia and underevaluation in additional indications.15
We have previously reported on the discovery of several seriesof novel and potent Btk inhibitors that possess exquisite selectivityfor Btk over other kinases.9−11,16 Their high potency and selectivity stems from the ability of compoundssuch as 1 to create an induced binding fit in the proteinvia a rearrangement of the activation loop.3 Other kinases, including members of the tyrosine kinase family,cannot rearrange in the exact same way due to differences in the aminoacid sequence within this loop.11 The tetrahydrobenzothiophenemoiety within 1, held rigidly in place by other contactsthe inhibitor makes with the protein, presents a hydrophobic surfacethat “attracts and sequesters” Y551, ultimately creatinga lipophilic specificity pocket (“H3”). A common featurein this series is the incorporation of a secondary amide that tethersthe distal bicyclic ring to the central benzene. We set out to addressmetabolism and permeability liabilities associated with the amidemoiety.
In particular, we hypothesized that molecules with anamide tethered back onto the tetrahydrobenzothiophene, such as 2a, would offer a molecule with one less exposed N–Hdonor and reduce the number of rotatable bonds, potentially improvingpotency and permeability. Crystal structures of related compoundsbound to Btk indicated the amide N–H was not interacting withthe protein.3 Additionally, we incorporateda hydroxyl group in the central benzene ring that was well positionedto interact with nearby K430 and D539 residues, with the hope of improvingbinding affinity. Table 1 shows the potencies of these compounds for Btk in a biochemicalassay, as well as their potencies in an in vitro mousesplenocyte CD86 cell based assay that was used as a downstream pharmacodynamicmarker for Btk activity (assay protocols in SI). Pleasingly, the newly generated tricyclic compound 2a was roughly 4-fold more potent against Btk than the uncyclized precursor 1. Compound 2b, which includes a hydroxymethylgroup on the central benzene ring, had a ∼10-fold increasein Btk binding potency than 2a and was roughly 40-foldmore potent than compound 1. With the improved potencyand/or decreasing lipophilicity, the lipophilic ligand efficiency(LLE) increased sequentially from 1 (3.6) to 2a (4.2) to 2b (5.8), indicating enhanced druglike properties.The cellular potency of compound 2b (IC50 =0.087 μM), as measured by inhibition of CD86 surface expressionon B cells, is 8-fold higher than that of 1 (IC50 = 0.74 μM). Additionally, 2b is 2-fold more orallybioavailable (90%) than 1 (45%) and has similarly lowclearance in rat.
Table 1
Improved Properties of Tricyclic H3Btk Inhibitors
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| IC50 (μM)a | Rat | |||||
|---|---|---|---|---|---|---|
| ID | Btk | CD86 | LLEb | hPPBc | CLd | F%e |
| 1 | 0.042 | 0.74 | 3.6 | 99% | 2 | 45% |
| 2a | 0.011 | 4.2 | 99% | |||
| 2b | 0.001 | 0.087 | 5.8 | 97% | 2 | 90% |
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aAssay protocols in Supporting Information (SI), n ≥ 2.
bLLE = pIC50(Btk)– cgLogD.
cHuman plasmaprotein binding.
dTotal clearance(mL/min/kg) at 1 mg/kg i.v. dose formulated using a mixture of EtOH/Cremophor/waterfor 1 (solution) or PEG400/EtOH/water for 2b (solutions).
eF% = oralbioavailability after a 5 mg/kg oral dose (n = 3)formulated using a mixture of EtOH and Cremophor for 1 (solution) or PEG400/EtOH/Tween80/water for 2b (suspension).
Modeling of 1 and 2b in the Btk catalytic domain is shown in Figure Figure11. The tricyclic system didnot alter the overall predicted ligand binding mode, and preservedthe interactions at the kinase selectivity H3 pocket with the neighboringhydrophobic residues. Specific interactions with Y551 and K430 weremaintained. The hydroxymethyl on the central benzene ring projectedinto a water-filled cavity, and formed H-bonds with K430 and D539.
Figure 1
Superpositionof modeled structures of 1 (magenta) and 2b (cyan) in the Btk catalytic domain. H-bonds to the protein are shownas black cylinders with dashed lines. The active site surface is showncolor coded by lipophilicity (green, nonpolar; purple, polar).
The success of our initial attemptsat creating improved Btk inhibitors by the employment of a tricyclicmoiety encouraged us to explore additional tricycles at this positionas well as carefully designed bicycles. Table 2 shows a selected subset of such compounds.Compounds 2b–6 are examples of inhibitorsthat contain distal 6–5–6 tricyclic ring systems. Sincethe H3 site is lipophilic, with nonpolar residues flanking much ofthis pocket, it is not surprising that the most potent compounds, 2b and 3 (Btk IC50 = 0.001 and 0.006μM respectively), contain all-carbon fused cyclohexane rings.
Table 2
SAR for H3 Groups
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aAssay protocol in SI, n ≥ 2.
bKinetic solubility was measured at pH 7.4.17
Compound 4, with a heteroatom in the right-hand saturated ring, displayed reducedpotency (Btk IC50 = 0.081 μM), while 5 and 6 were much less potent, presumably due to thereduced lipophilicity of the tricycle. Modeling indicated that therewas an opportunity to further flesh out the H3 pocket and that gemdimethyl substituted 6–5–5 systems might offer someadvantages by occupying more of the lipophilic H3 pocket. The resulting6–5–5 compounds 7 and 8 of 2b and 3, respectively, were equipotent to slightlymore potent against Btk (IC50 = 0.002 μM), and bothhad improved cell potencies.
We also examined bicyclic 6–6fused (9), 5–5 fused (10-11), and 5–6 fused (12) ring systems containingappropriately placed tert-butyl groups to extendinto the H3 pocket. Among this group, the 5–5, 5–6 fused 10 and 12 had the highest enzyme binding potency(Btk IC50’s = 0.003 μM) but were relativelyless potent in the CD86 cellular assay.
Finally, we surveyed7–6 ring systems (13 and 14). Thesecompounds were less appealing due to their decreased biochemical andcell potencies. The cell potencies of all compounds mostly trackedwith biochemical potencies, with the Btk/CD86 IC50 ratioranging from 6- (4) to 64- (10) fold. Theonly major outlier was the bicyclic compound 12, whichhad a cell shift of 400-fold. Presumably, this shift was due to differencesin plasma protein binding and cell permeability of this compound.Other researchers have reported on a variety of bicyclic H3 moietieswithin alternate series;18−20 however, we are the first groupto describe highly potent and Btk-selective tricyclic 6–5–6and 6–5–5 compounds.
With a variety of novel tricycliccompounds in hand that had excellent potency for Btk, we focused ourefforts on designing compounds with improved physiochemical properties.As demonstrated in Table 2, although compounds 2b, 7, 8, and 9 had the best cellular potency (CD86IC50 < 100 nM), they unfortunately all had low kineticsolubility (<2 μM) at physiological pH. Kinetic solubilityas measured in an internal high throughput assay17 was used as an initial gauge of intrinsic solubility. Lowsolubility is a primary cause of reduced oral bioavailability of thecrystalline materials preferred for clinical development, and oftenpresents formulation challenges in dose escalations for safety studies.This was indeed the case for many compounds in this chemical series.To find compounds with improved solubility, modifications of the left-handportion of the inhibitor that extends into a partially solvent exposedarea of the protein region (“H2”, Figure Figure11) were explored and found to be well tolerated.Of the many compounds generated,21 we determinedthat compounds with a substituted pyridinopiperazine group (Table 3), as opposed to thepyrimidine of the previous compounds (Table 2), offered an exciting new subseries withmuch improved kinetic solubility.
Table 3
Combination of theBest H2 and H3 Moieties for Optimal Potency and Druglike Properties
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aAssay protocolin SI, n ≥ 2.
bProjected hepatic clearanceusing human or rat hepatocytes.
cKinetic solubility was measured at pH 7.4.17
dMeasured permeabilityusing Madin-Darby Canine Kidney (MDCK) Epithelial cell lines, A toB; MOD: 1–10 (10–6 cm/s) and HIGH: >10(10–6 cm/s).
eTotal clearance (mL/min/kg) at 1 mg/kg i.v. dose formulated usinga mixture of PEG400/ethanol/water for 7, 15, and 17–20 (solution).
fF% = oral bioavailability after 5 mg/kgoral dose (n = 3) formulated using a mixture of PEG400/ethanol/Tween80/waterfor 7 (suspension), PEG400/ethanol/water for 17 (suspension), 15, 18–20 (solution).
A small subsetof compounds containing combinations of the best H2 and H3 groupsare highlighted in Table 3. Installing a tertiary basic amine containing left-hand H2,which is primarily protonated at neutral pH, indeed helped improvethe solubility from 1.4 μM (7) to 18 μM (15). Reducing the basicity from a calculated pKa of 7.8 (15) to 6.3 (16, substitutedwith an oxetane)22 abrogated the improvedsolubility. This prompted us to focus on H3 groups with higher polaritythan that of 7. Gratifyingly, all four compounds containinga more polar tetrahydroindole H3 group (17-20) maintained high kinetic solubility regardless of the amine basicity.However, the moderate CD86 cellular potencies of 17 and 18 (IC50‘s of 0.107 and 0.137 μM,respectively) mirrored that of the 0.2 μM potency seen for 3, which bears the same polar H3 group. A potency breakthroughwas realized when a single fluorine atom was added to the middle linkerbenzene ring (19–20). This fluorine is well positionedto engage the backbone carbonyl carbon of G409 in a dipole–dipoleinteraction (Figure s1 in the SI), furtherstabilizing the binding orientation of these inhibitors in the Btkcatalytic domain. The resultant CD86 cellular potency improved 5-foldand 13-fold for the two pairs 17 → 19 and 18 → 20, respectively.
All compounds in Table 3, except 17, were low to moderately cleared and hadreasonable bioavailability in in vivo rat PK studies. In vitro hepatic clearance represented by RHEP data underestimatedthe in vivo clearance; however, the relative stabilitytrend was consistent from in vitro to invivo studies. It was also pleasing to see that human hepaticclearance ranged from low to moderate. Given the totality of dataincluding safety assessment (not discussed here), compounds 7 (G-744) and 20 rose to the topof the list with the most balanced overall profile.
In additionto potency and druglike properties, a prominent goal of developinga clinically viable kinase inhibitor lies in controlling selectivity.Poor selectivity may have a profound effect on drug safety, especiallyfor nononcology indications where chronic dosing requires an exquisitelyclean safety profile. Therefore, both G-744 and 20 were profiled against a panel of 285 active recombinanthuman kinases. In particular, G-744 demonstrated >1000-foldBtk biochemical selectivity against all kinases tested except forEphA7 and Fgr, against which it still showed robust selectivity of428-fold and 868-fold, respectively (Figure s3 in the SI). Due to G-744’s superb kinase selectivity(superior to 20), we realized it could be an excellenttool molecule to probe the biology of Btk, as the results would notbe confounded by off-target activity and the need for interpretation.Thus, we performed a full characterization of this molecule, withkey data summarized in Table 4. In addition to preventing cellular functions in murine B-cellssuch as B-cell receptor (BCR)-mediated CD86 induction with an EC50 of 64 nM, G-744 also inhibited BCR-stimulatedB-cell proliferation in human B-cells (EC50 = 22 nM). Inhuman monocytes, production of the inflammatory cytokine TNFαfollowing activation with immune complexes was abrogated by G-744 (EC50 = 33 nM). In human whole blood, G-744 demonstrated potent inhibition of BCR-stimulated CD69expression on B-cells with an EC50 of 87 nM.
Table 4
Additional G-744 Potency Data (mean ± SEM)
| Assay | Ki,app or EC50 (nM) |
|---|---|
| Btk biochemical, (Ki,app) | 1.28±0.13 [n=3] |
| Mouse splenocyte B cell CD86 | 55 and 75 [n=2] |
| Human Whole Blood B cell CD69 | 87±30 [n=11] |
| Human B cell proliferation | 22±3 [n=17] |
| Humanmonocyte TNFα production | 33±6 [n=12] |
Open in a separate window
In pharmaco*kinetic experiments, G-744 exhibited low to moderate clearance in four preclinicalspecies (Table 5).Sufficient oral exposures were achievable using a crystalline formulationin both mouse and rat despite low kinetic solubility.
Table 5
Preclinical DMPK Profiling of G-744
| In vitro | In vivo | |||
|---|---|---|---|---|
| Species | LM CLhepa | Hep CLhepb | CLc | F%d |
| mouse | 35 | 2 | 22 | 45e –77f |
| rat | 18 | 3 | 16 | 23e – 37f |
| dog | 15 | 1 | 7 | 27f |
| cyno | 18 | 31 | 17 | |
| human | 8 | 11 | ||
Open in a separate window
aProjected hepaticclearance using liver microsomes (mL/min/kg).
bProjected hepatic clearance using hepatocytes (mL/min/kg).
cTotal clearance invivo (mL/min/kg).
dF% = oral bioavailability after 5 (amorphous) or 100 mg/kg (crystalline)dose in mouse; 5 (amorphous) or 100 mg/kg (crystalline) dose in rat;5 mg/kg dose in dog (n = 3).
eMethylcellulose/Tween80/water suspension of crystallinefree base material.
fHydroxypropylmethethylcellulose/Nacitrate/water pH 3 suspension of amorphous material.
Given the favorable DMPK profileof G-744 in rat, we examined its efficacy in the developingcollagen-induced arthritis (CIA) model in Lewis rat.3,23 Oral dosing with G-744 at 6.25, 12.5, and 25 mg/kgb.i.d. maintained plasma concentrations above the IC50,IC70, and IC90, respectively, for inhibitionof Btk Y223 phosphorylation in whole blood (Figure s2 in the SI). As shown in Figure Figure22, all three doses resulted in a significantdose-dependent inhibition of ankle thickness between day 10 and day17 (onset of increase in ankle diameter on day 9). The 25 mg/kg dose(97% inhibition of the area under the ankle thickness vehicle curve)showed comparable efficacy to dexamethasone. In naïve ratstreated with vehicle, the ankle diameters did not change over thecourse of the study and ankles from normal rats were significantlydifferent (P < 0.05) compared with the CIA ratstreated with vehicle. In addition, G-744 was also highlyefficacious in preventing Interferon α-driven lupus nephritis.24
Figure 2
Results from a CIA study in rats. Treatment with G-744 protects Lewis rats from collagen-induced arthritis.Female Lewis rats (n = 10 per group) with developingCIA were dosed orally with G-744 as indicated (b.i.d.)or with 0.05 mg/kg dexamethasone daily starting on day 0. Daily anklediameter measurements are shown as mean ± SEM and were significantly(by ANOVA) reduced toward normal for all drug-treated rats (significantdays 10–17) as compared to the vehicle control.
In summary, orally bioavailable Btk inhibitorswith novel tricyclic head groups were discovered through structureand property based drug design. Improved molecules were discovered,and an outstanding tool molecule, G-744, was identifiedwith excellent potency, favorable DMPK properties, and superb kinaseselectivity. G-744 demonstrated efficacy equivalent toDexamethasone in a rat CIA model at 25 mg/kg b.i.d. dosing. Such findingsfurther solidified our commitment to Btk as a therapeutic target.The chemistry culminating in a clinical candidate will be describedin a subsequent manuscript.
Acknowledgments
We aregrateful to analytical, purification chemistry and compound managementgroup for compound characterization, purification, and handling.
Glossary
Abbreviations
| Btk | Bruton’s tyrosine kinase |
| RA | Rheumatoid arthritis |
| SLE | systemic lupuserythematosus |
| MS | multiple sclerosis |
| MCL | mantle cell lymphoma |
| CLL | chronic lymphocytic leukemia |
| BCR | B-cell receptor |
| DMPK | drug metabolism and pharmaco*kinetics |
| CIA | collagen-induced arthritis |
| b.i.d. | twice a day |
| SEM | standard errorof the mean |
Biographies
•
Xiaojing Wang received a B.S. degree from Peking University,a Ph.D. in Organic Chemistry from University of Florida under thesupervision of Kenan Professor Alan R. Katritzky, and was a PostdoctoralFellow at RTI International with Dr. C. Edgar Cook. Since then, Xiaojinghas pursued drug discovery of various disease indications at ISIS(now Ionis), Scios/Johnson and Johnson, and Genentech/Roche. Xiaojingis currently a Senior Scientist of Discovery Chemistry at Genentechand has led multidisciplinary teams into nominating several clinicalcandidates as a project team lead. Xiaojing is an inventor and authorof over 40 patents and research publications.
•
Wendy B. Young received a B.A./M.S. in chemistry fromWFU under the guidance of Huw Davies, a Ph.D. from Princeton Universityunder the direction of E. C. Taylor, and was a Postdoctoral Fellowat Sloan-Kettering in the laboratory of Samuel Danishefsky. Sincethen, Wendy has led drug discovery efforts at both small biotech firms(Axys/Celera) and larger pharma companies (Genentech/Roche). Wendyis currently Vice President of Discovery Chemistry at Genentech whereher teams have produced numerous drug candidates in multiple diseaseindications. She is listed as an inventor or author on over 70 patentsand research publications. Wendy is currently the 2017 elected Chairof the ACS MEDI division.
Supporting Information Available
The Supporting Information is available free ofcharge on the ACS Publicationswebsite at DOI: 10.1021/acsmedchemlett.7b00103.
Physiochemical properties, experimentalprocedures, compound characterization, assay protocols, PK–PDrelationship, and full kinome data (PDF)
Notes
Thanks to Genentech, a member ofthe Roche Group for the research funds.
Notes
The authors declareno competing financial interest.
Supplementary Material
ml7b00103_si_001.pdf(1.4M, pdf)
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