Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial.

PURPOSE: Injection of pharmacotherapy into the suprachoroidal space, between the sclera and choroid, is an alternative delivery technique developed with the rationale of providing higher drug concentrations to posterior ocular structures compared with other intraocular and periocular injection procedures. This study was conducted to evaluate the safety and efficacy of suprachoroidally injected triamcinolone acetonide formulation (CLS-TA), a suspension of triamcinolone acetonide, in improving vision among patients with noninfectious uveitis complicated by macular edema (ME). DESIGN: Phase 3 masked, randomized trial. PARTICIPANTS: One hundred sixty patients with ME secondary to noninfectious uveitis. Patients were required to have a best-corrected visual acuity (BCVA) of 5 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent, 20/800) and 70 or fewer ETDRS letters read (Snellen equivalent, 20/40) in the study eye. METHODS: Patients were randomized 3:2 to suprachoroidally injected CLS-TA or sham treatment, with administrations at day 0 and week 12. MAIN OUTCOME MEASURES: The primary end point was improvement from baseline of 15 or more ETDRS letters in BCVA at week 24. The secondary end point was reduction from baseline in central subfield thickness (CST) at week 24. RESULTS: In the CLS-TA arm, 47% of patients gained 15 or more ETDRS letters in BCVA versus 16% in the control arm (P < 0.001), meeting the primary end point. Mean reductions in CST from baseline were 153 µm versus 18 µm (P < 0.001). No serious adverse events (AEs) related to treatment were reported. Corticosteroid-associated AEs of elevated intraocular pressure occurred in 11.5% and 15.6% of the CLS-TA and control groups, respectively. Cataract AE rates were comparable (7.3% and 6.3%, respectively). CONCLUSIONS: Patients in the CLS-TA study arm experienced clinically significant improvement in vision relative to the sham procedure, demonstrating the efficacy of suprachoroidal injection of CLS-TA for the treatment of ME in a vision-threatening disorder.

Suprachoroidal and Subretinal Injections of AAV Using Transscleral Microneedles for Retinal Gene Delivery in Nonhuman Primates.

Retinal gene therapy using adeno-associated viruses (AAVs) is constrained by the mode of viral vector delivery. Intravitreal AAV injections are impeded by the internal limiting membrane barrier, while subretinal injections require invasive surgery and produce a limited region of therapeutic effect. In this study, we introduce a novel mode of ocular gene delivery in rhesus macaques using transscleral microneedles to inject AAV8 into the subretinal or suprachoroidal space, a potential space between the choroid and scleral wall of the eye. Using in vivo imaging, we found that suprachoroidal AAV8 produces diffuse, peripheral expression in retinal pigment epithelial (RPE) cells, but it elicited local infiltration of inflammatory cells. Transscleral subretinal injection of AAV8 using microneedles leads to focal gene expression with transduction of RPE and photoreceptors, and minimal intraocular inflammation. In comparison, intravitreal AAV8 shows minimal transduction of retinal cells, but elicits greater systemic humoral immune responses. Our study introduces a novel mode of transscleral viral delivery that can be performed without vitreoretinal surgery, with focal or diffuse transgene expression patterns suitable for different applications. The decoupling of local and systemic immune responses reveals important insights into the immunological consequences of AAV delivery to different ocular compartments surrounding the blood-retinal barrier.

Suprachoroidally injected pharmacological agents for the treatment of chorio-retinal diseases: a targeted approach.

Delivery of pharmaceuticals to the posterior segment presents challenges that arise from the anatomy and clearance pharmacokinetics of the eye. Systemic and several local administration options [topical, periocular, intravitreal (IVT) and subretinal] are in clinical use, each with a unique benefit to risk profile shaped by factors including the administered agent, frequency of dosing, achievable pharmaceutical concentrations within posterior segment structures versus elsewhere in the eye or the body, invasiveness of the procedure and the inherent challenges with some administration methods. The use of the suprachoroidal space (SCS), which is the region between the sclera and the choroid, is being explored as a potential approach to target pharmacotherapies to the posterior segment via a minimally invasive injection procedure. Preclinical data on agents such as vascular endothelial growth factor inhibitors and triamcinolone acetonide (TA) indicate that administration via suprachoroidal injection results in more posterior distribution of the pharmacologic agent, with higher exposure to the sclera, choroid, retinal pigment epithelium cells and retina, and lesser exposure to the anterior segment, than observed with IVT administration. Based in part on these findings, clinical trials have explored the efficacy and safety of suprachoroidal administration of pharmacologic therapies in conditions affecting the posterior segment. Data on a proprietary formulation of TA administered by suprachoroidal injection show improvement in anatomic and visual outcomes in subjects with noninfectious uveitis, with the potential to mitigate the known risks of cataract and increased intraocular pressure (IOP) associated with the use of intraocular corticosteroids. Suprachoroidal administration appears to be a promising treatment modality and is also in the early stages of investigation for other possible applications, such as injection of antiglaucoma agents into the anterior SCS for long-lasting control of elevated IOP, and as a mode of delivery for gene- or cell-based therapies for retinal disorders.

SUPRACHOROIDAL INJECTION OF TRIAMCINOLONE ACETONIDE, CLS-TA, FOR MACULAR EDEMA DUE TO NONINFECTIOUS UVEITIS: A Randomized, Phase 2 Study (DOGWOOD).

PURPOSE: Evaluate a single suprachoroidal injection of a proprietary triamcinolone acetonide suspension, CLS-TA, in subjects with macular edema due to noninfectious uveitis. METHODS: Randomized, controlled, masked Phase 2 study. Safety and efficacy of a single suprachoroidal injection of CLS-TA (4.0 and 0.8 mg in a 4:1 ratio) were assessed at 1 and 2 months after injection. The primary efficacy endpoint was change in central subfield thickness from baseline to Month 2, assessed by spectral domain optical coherence tomography. RESULTS: Twenty-two adults were enrolled. The primary endpoint was met in subjects who received suprachoroidal injection of CLS-TA 4.0 mg, mean central subfield thickness significantly decreased from baseline by 135 µm and 164 µm at Month 1 (P = 0.0056) and Month 2 (P = 0.0017), respectively. At Month 2, 69% of subjects who received 4.0 mg experienced ≥20% reduction in central subfield thickness, and 65% had improvement of best-corrected visual acuity of ≥5 Early Treatment Diabetic Retinopathy Study letters, with a mean improvement of 9.2 letters (P = 0.0004). Safety analyses supported acceptable safety/tolerability, with no corticosteroid-related increases in intraocular pressure. CONCLUSION: A single suprachoroidal injection of CLS-TA (4.0 mg; 0.1 mL) in subjects with macular edema due to noninfectious uveitis was well-tolerated, significantly reduced central subfield thickness from baseline at 2 months, and significantly improved visual acuity.

Suprachoroidal Space Alterations Following Delivery of Triamcinolone Acetonide: Post-Hoc Analysis of the Phase 1/2 HULK Study of Patients With Diabetic Macular Edema.

BACKGROUND AND OBJECTIVE: To study anatomic changes in the suprachoroidal space (SCS) following suprachoroidal injection of CLS-TA, triamcinolone acetonide injectable suspension. PATIENTS AND METHODS: Eyes with diabetic macular edema receiving CLS-TA were imaged serially using anterior segment spectral-domain optical coherence tomography to examine the SCS. RESULTS: At the final imaging session, the SCS was not significantly different in study eyes (n = 14; 8.4 µm) compared to fellow eyes (n = 10; 8.1 µm; P = .698). Two eyes were imaged immediately before and 30 minutes after suprachoroidal injections; in these eyes, mean suprachoroidal width increased significantly following CLS-TA injection, 9.9 µm to 75.1 µm (P < .001), and subsequently returned to 14.9 µm 1 month after the final injection (P = .221). CONCLUSION: Suprachoroidal CLS-TA injection caused a measurable increase in the SCS, which returned to preinjection levels by 1 month following injection with no apparent lasting impact on SCS anatomy. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:692-697.].

Choroidal Changes After Suprachoroidal Injection of Triamcinolone Acetonide in Eyes With Macular Edema Secondary to Retinal Vein Occlusion.

PURPOSE: To evaluate choroidal and suprachoroidal changes following suprachoroidal injection of triamcinolone acetonide injectable suspension (CLS-TA), in eyes with macular edema due to retinal vein occlusion (RVO). DESIGN: Prospective cohort study within a randomized, controlled phase 2 clinical trial. METHODS: Enhanced depth imaging optical coherence tomography (EDI-OCT) images were analyzed from 38 eyes of 38 treatment-naïve patients with macular edema due to RVO, enrolled in the prospective Suprachoroidal Injection of Triamcinolone Acetonide with Intravitreal Aflibercept in Subjects with Macular Edema Due to Retinal Vein Occlusion (TANZANITE) study who received either a suprachoroidal injection of CLS-TA with an intravitreal injection of aflibercept (combination arm) or only an intravitreal injection of aflibercept (monotherapy arm), followed by monthly intravitreal aflibercept injections in both arms based on pro re nata criteria. RESULTS: Macular choroidal thickness measured to the outer choroidal vessel lumen (vascular choroidal thickness, VCT), outer choroid stroma (stromal choroidal thickness, SCT), or inner scleral border (total choroidal thickness, TCT) showed no significant changes over 3 months in both study arms (P = .231-.342). Eyes that received combination therapy showed a trend toward thickening of the suprachoroidal space (SCS) compared with monotherapy alone (13.4 µm vs 5.3 µm at 3 months; P = .077). In the 15 eyes that demonstrated a visible SCS at baseline, the SCS expanded significantly after suprachoroidal CLS-TA injection (16.2 µm to 27.8 µm at 3 months; P = .033). CONCLUSIONS: Suprachoroidal injection of CLS-TA does not alter choroidal thickness in eyes with macular edema due to RVO, but may result in expansion of the SCS.

Suprachoroidal Triamcinolone Acetonide for Retinal Vein Occlusion: Results of the Tanzanite Study.

PURPOSE: To compare the safety and efficacy of treatment with suprachoroidal triamcinolone acetonide (CLS-TA) plus intravitreal aflibercept vs. treatment with aflibercept alone in patients with macular edema due to retinal vein occlusion (RVO). DESIGN: Randomized masked controlled clinical trial. SUBJECTS: Forty-six patients with RVO. METHODS: Subjects were randomized 1:1 to suprachoroidal injection of CLS-TA plus intravitreal aflibercept (combination arm) or sham suprachoroidal injection plus aflibercept (aflibercept arm), followed by aflibercept as needed at months 1, 2, and 3 in each arm. MAIN OUTCOME MEASURES: The primary efficacy end point was the number of protocol-required aflibercept re-treatments through month 3. Secondary outcomes included mean improvement from baseline best-corrected visual acuity (BCVA), central subfield thickness (CST), and the percentage of participants with CST ≤310 µm at each time point. RESULTS: The number of re-treatments were reduced in the combination arm compared with that in the aflibercept arm (23 vs. 9; -61%; P = 0.013) and the percentage of participants requiring no re-treatments was increased (78% vs. 30%; P = 0.003). The mean improvement from baseline BCVA letter score in combination vs. that in the aflibercept arms was 16.1 vs. 11.4 (P = 0.20) at month 1, 20.4 vs. 11.9 (P = 0.04) at month 2, and 18.9 vs. 11.3 (P = 0.09) at month 3. The mean baseline CST in the combination arm (731.1 µm) decreased into the normal range at month 1 (284.7 µm) and remained there at months 2 and 3 (272.4 µm and 285.4 µm). The mean baseline CST (727.5 µm) in the aflibercept arm decreased to 322.8 µm at month 1 and increased at months 2 and 3 (383.4 µm and 384.6 µm). Edema resolution (CST ≤ 310 µm) occurred in 87.0%, 87.0%, and 78.3% of participants in the combination arm at months 1, 2, and 3, respectively, vs. 56.5%, 47.8%, and 47.8% of participants in the aflibercept arm. In the combination arm, 1 participant had cataract progression and 4 (2 with preexistent glaucoma) had increased intraocular pressure that was controlled with topical medication. CONCLUSIONS: Combination intravitreal aflibercept and suprachoroidal CLS-TA is well tolerated and significantly reduces the need for additional intravitreal aflibercept injections over a 3-month period in patients with RVO. Preliminary evidence suggests that combination therapy may sustain edema resolution and improve visual outcomes.

Suprachoroidal Corticosteroid Administration: A Novel Route for Local Treatment of Noninfectious Uveitis.

PURPOSE: To evaluate the safety, tolerability, and preliminary efficacy of suprachoroidal injection of triamcinolone acetonide (TA) in patients with noninfectious uveitis. METHODS: In this Phase 1/2 open-label clinical study, a single suprachoroidal injection of 4-mg TA in 100 µL was performed in the study eye of patients with noninfectious intermediate, posterior, or pan-uveitis, and follow-up obtained for 26 weeks. RESULTS: Nine individuals with chronic uveitis were enrolled. There were 38 reported adverse events (AEs); most were mild or moderate in severity. Approximately half the AEs were ocular. The most common AE was reported by four subjects who experienced ocular pain at or near the time of the injection. All systemic AEs were unrelated to study drug. No steroid-related increases in intraocular pressure (IOP) were observed and no subject required IOP-lowering medication. All eight efficacy-evaluable subjects had improvements in visual acuity. Four subjects, who did not need additional therapy, had on average a greater than 2-line improvement in visual acuity through week 26. Three of four had macular edema at baseline, and two of three had at least a 20% reduction in macular edema at week 26. CONCLUSIONS: The safety and preliminary efficacy data support further investigations of suprachoroidally administered TA as a therapeutic option for the treatment of noninfectious uveitis. TRANSLATIONAL RELEVANCE: Targeted suprachoroidal administration of corticosteroid is a potential local route for the treatment of ocular inflammatory disease, which merits further investigation. (www.ClinicalTrials.gov, NCT01789320).

Aerosolized phosphoinositide 3-kinase gamma/delta inhibitor TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease.

Phosphatidylinositol 3-kinases (PI3Ks) are key elements in the signaling cascades that lie downstream of many cellular receptors. In particular, PI3K delta and gamma isoforms contribute to inflammatory cell recruitment and subsequent activation. For this reason, in a series of preclinical studies, we tested the potential of a recently developed small-molecule inhibitor of these two isoforms, TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol], as a form of anti-inflammatory therapy for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). To determine pharmacokinetic profiles, aerosolized formulations of the drug were delivered to mice by a nose-only inhalation route, yielding high pulmonary TG100-115 levels with minimal systemic exposure. Safety assessments were favorable, with no clinical or histological changes noted after 21 days of daily dosing. In a murine asthma model, aerosolized TG100-115 markedly reduced the pulmonary eosinophilia and the concomitant interleukin-13 and mucin accumulation characteristic of this disease. As a functional benefit, interventional dosing schedules of this inhibitor also reduced airway hyper-responsiveness. To model the pulmonary neutrophilia characteristic of COPD, mice were exposed to either intranasal lipopolysaccharide or inhaled smoke. Aerosolized TG100-115 again inhibited these inflammatory patterns, most notably in the smoke model, where interventional therapy overcame the steroid-resistant nature of the pulmonary inflammation. In conclusion, aerosolized TG100-115 displays pharmacokinetic, safety, and biological activity profiles favorable for further development as a therapy for both asthma and COPD. Furthermore, these studies support the hypothesis that PI3K delta and gamma are suitable molecular targets for these diseases.

Development of novel benzotriazines for drug discovery.

BACKGROUND: The synthesis of novel benzotriazine heterocycles was developed independently around the same time by Bischler, Bamberger and Arndt. Over the years, different groups have reported the synthesis of benzotriazine based compounds. OBJECTIVE: This literature review gives an update on recent benzotriazine compounds and their applications. CONCLUSION: The benzotriazine core has been used in various drug discovery projects including anticancer, anti-inflammatory and antimalarial programs. Recently, the benzotriazine core was used to develop selective kinase inhibitors targeting SRC, VEGFr2, BCR-ABL and BCR-ABL-T315I. Two benzotriazine based compounds, tirapazamine for the treatment of cancer and TG100801 for the treatment of age-related macular degeneration, have entered clinical trials.

Inhibitors of ABL and the ABL-T315I mutation.

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder caused by increased and unregulated growth of myeloid cells in the bone marrow, and the accumulation of excessive white blood cells. Abelson tyrosine kinase (ABL) is a non-receptor tyrosine kinase involved in cell growth and proliferation and is usually under tight control. However, 95% of CML patients have the ABL gene from chromosome 9 fused with the breakpoint cluster (BCR) gene from chromosome 22, resulting in a short chromosome known as the Philadelphia chromosome. This Philadelphia chromosome is responsible for the production of BCR-ABL, a constitutively active tyrosine kinase that causes uncontrolled cellular proliferation. An ABL inhibitor, imatinib, was approved by the FDA for the treatment of CML, and is currently used as first line therapy. However, a high percentage of clinical relapse has been observed due to long term treatment with imatinib. A majority of these relapsed patients have several point mutations at and around the ATP binding pocket of the ABL kinase domain in BCR-ABL. In order to address the resistance of mutated BCR-ABL to imatinib, 2(nd) generation inhibitors such as dasatinib, and nilotinib were developed. These compounds were approved for the treatment of CML patients who are resistant to imatinib. All of the BCR-ABL mutants are inhibited by the 2(nd) generation inhibitors with the exception of the T315I mutant. Several 3(rd) generation inhibitors such as AP24534, VX-680 (MK-0457), PHA-739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113 are being developed to target the T315I mutation. The early results from these compounds are encouraging and it is anticipated that physicians will have additional drugs at their disposal for the treatment of patients with the mutated BCR-ABL-T315I. The success of these inhibitors has greater implication not only in CML, but also in other diseases driven by kinases where the mutated gatekeeper residue plays a major role.

Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits.

Retinal and choroidal vascular diseases, with their associated abnormalities in vascular permeability, account for the majority of patients with vision loss in industrialized nations. VEGF is upregulated in ischemic retinopathies such as diabetes and is known to dramatically alter vascular permeability in a number of nonocular tissues via Src kinase-regulated signaling pathways. VEGF antagonists are currently in clinical use for treating the new blood vessels and retinal edema associated with neovascular eye diseases, but such therapies require repeated intraocular injections. We have found that vascular leakage following intravitreal administration of VEGF in mice was abolished by systemic or topical delivery of what we believe is a novel VEGFR2/Src kinase inhibitor; this was confirmed in rabbits. The relevance of Src inhibition to VEGF-associated alterations in vascular permeability was further substantiated by genetic studies in which VEGF injection or laser-induced vascular permeability failed to augment retinal vascular permeability in Src-/- and Yes-/- mice (Src and Yes are ubiquitously expressed Src kinase family members; Src-/- and Yes-/- mice lacking expression of these kinases show no vascular leak in response to VEGF). These findings establish a role for Src kinase in VEGF-mediated retinal vascular permeability and establish a potentially safe and painless topically applied therapeutic option for treating vision loss due to neovascular-associated retinal edema.

Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera.

We report that TG101348, a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of approximately 3 nM, shows therapeutic efficacy in a murine model of myeloproliferative disease induced by the JAK2V617F mutation. In treated animals, there was a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis. There were no apparent toxicities and no effect on T cell number. In vivo responses were correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden assessed by quantitative genomic PCR, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction as assessed by flow cytometric measurement of phosphorylated Stat5.

Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors.

Polycythemia Vera (PV) is a myeloproliferative disorder (MPD) that is commonly characterized by mutant JAK2 (JAK2V617F) signaling, erythrocyte overproduction, and a propensity for thrombosis, progression to myelofibrosis, or acute leukemia. In this study, JAK2V617F expression by human hematopoietic progenitors promoted erythroid colony formation and erythroid engraftment in a bioluminescent xenogeneic immunocompromised mouse transplantation model. A selective JAK2 inhibitor, TG101348 (300 nM), significantly inhibited JAK2V617F+ progenitor-derived colony formation as well as engraftment (120 mg/kg) in xenogeneic transplantation studies. TG101348 treatment decreased GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibited STAT5 as well as GATA S310 phosphorylation. Thus, TG101348 may be an effective inhibitor of JAK2V617F+ MPDs in clinical trials.

Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema.

Age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions are complicated by neovascularization and macular edema. Multi-targeted kinase inhibitors that inhibit select growth factor receptor tyrosine kinases and/or components of their down-stream signaling cascades (such as Src kinases) are rationale treatment strategies for these disease processes. We describe the discovery and characterization of two such agents. TG100572, which inhibits Src kinases and selected receptor tyrosine kinases, induced apoptosis of proliferating endothelial cells in vitro. Systemic delivery of TG100572 in a murine model of laser-induced choroidal neovascularization (CNV) caused significant suppression of CNV, but with an associated weight loss suggestive of systemic toxicity. To minimize systemic exposure, topical delivery of TG100572 to the cornea was explored, and while substantial levels of TG100572 were achieved in the retina and choroid, superior exposure levels were achieved using TG100801, an inactive prodrug that generates TG100572 by de-esterification. Neither TG100801 nor TG100572 were detectable in plasma following topical delivery of TG100801, and adverse safety signals (such as weight loss) were not observed even with prolonged dosing schedules. Topical TG100801 significantly suppressed laser-induced CNV in mice, and reduced fluorescein leakage from the vasculature and retinal thickening measured by optical coherence tomography in a rat model of retinal vein occlusion. These data suggest that TG100801 may provide a new topically applied treatment approach for ocular neovascularization and retinal edema.

Development of prodrug 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration.

Age-related macular degeneration (AMD) is one of the leading causes of loss of vision in the industrialized world. Attenuating the VEGF signal in the eye to treat AMD has been validated clinically. A large body of evidence suggests that inhibitors targeting the VEGFr pathway may be effective for the treatment of AMD. Recent studies using Src/YES knockout mice suggest that along with VEGF, Src and YES play a crucial role in vascular leak and might be useful in treating edema associated with AMD. Therefore, we have developed several potent benzotriazine inhibitors designed to target VEGFr2, Src, and YES. One of the most potent compounds is 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-1-yl-ethoxy)phenylamino]benzo[1,2,4]triazin-7-yl}phenol ( 5), a dual inhibitor of both VEGFr2 and the Src family (Src and YES) kinases. Several ester analogues of 5 were prepared as prodrugs to improve the concentration of 5 at the back of the eye after topical administration. The thermal stability of these esters was studied, and it was found that benzoyl and substituted benzoyl esters of 5 showed good thermal stability. The hydrolysis rates of these prodrugs were studied to analyze their ability to undergo conversion to 5 in vivo so that appropriate concentrations of 5 are available in the back-of-the-eye tissues. From these studies, we identified 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl benzoate ( 12), a topically administered prodrug delivered as an eye drop that is readily converted to the active compound 5 in the eye. This topically delivered compound exhibited excellent ocular pharmacokinetics and poor systemic circulation and showed good efficacy in the laser induced choroidal neovascularization model. On the basis of its superior profile, compound 12 was advanced. It is currently in a clinical trial as a first in class, VEGFr2 targeting, topically applied compound for the treatment of AMD.

The design and preliminary structure-activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T315I enzymes.

We describe the design, synthesis and structure-activity relationship studies in optimizing a series of benzotriazine compounds as potent inhibitors of both Abl and Abl-T315I enzymes. The design includes targeting of an acid functional residue on the alphaC-helix that is available only upon kinase activation. This designed interaction provides an advantage in overcoming the challenges arising from the T315I mutation of Abl and transforms poor (ca. 10 microM) inhibitors into those with low nM potency.

Discovery of 3,3'-(2,4-diaminopteridine-6,7-diyl)diphenol as an isozyme-selective inhibitor of PI3K for the treatment of ischemia reperfusion injury associated with myocardial infarction.

In studies aimed toward identifying effective and safe inhibitors of kinase signaling cascades that underlie ischemia/reperfusion (I/R) injury, we synthesized a series of pteridines and pyridopyrazines. The design strategy was inspired by the examination of naturally occurring PI3K inhibitors such as wortmannin and quercetin, and building a pharmacophore-based model used for optimization. Structural modifications led to hybrid molecules which incorporated aminopyrimidine and aminopyridine moieties with ATP mimetic characteristics into the pharmacophore motifs to modulate kinase affinity and selectivity. Elaborations involving substitutions of the 2 and 4 positions of the pyrimidine or pyridine ring and the 6 and 7 positions of the central pyrazine ring resulted in in vivo activity profiles which identified potent inhibitors of vascular endothelial growth factor (VEGF) induced vascular leakage. Pathway analysis identified a diaminopteridine-diphenol as a potent and selective phosphatidylinositol-3-kinase (PI3K) inhibitor. The structure-activity relationship studies of various analogues of diaminopteridine-diphenol-based on biochemical assays resulted in potent inhibitors of PI3K.