A5074805538- Cell Adhesion Molecules Research
- Retinal Diseases and Treatments
- Protease and Inhibitor Mechanisms
- Peptidase Inhibition and Analysis
- Synthetic Organic Chemistry Methods
- DNA and Nucleic Acid Chemistry
- Complement system in diseases
- Radiopharmaceutical Chemistry and Applications
- Glaucoma and retinal disorders
- Bone Metabolism and Diseases
- Chemical Reaction Mechanisms
- Nitric Oxide and Endothelin Effects
- Cancer, Hypoxia, and Metabolism
- Receptor Mechanisms and Signaling
- Axon Guidance and Neuronal Signaling
- Coordination Chemistry and Organometallics
- Synthesis and Biological Evaluation
- Renin-Angiotensin System Studies
- Asymmetric Synthesis and Catalysis
- Synthesis of Organic Compounds
- Cancer therapeutics and mechanisms
- Quinazolinone synthesis and applications
- Renal Diseases and Glomerulopathies
- Synthesis and Catalytic Reactions
- Radical Photochemical Reactions
Peptidream (Japan)
2019-2024
Novartis (United States)
2018-2020
Novartis (Japan)
2007-2019
Novartis (Switzerland)
2007-2014
Toho University
2005-2008
Novartis Institutes for BioMedical Research
2008
Novartis (Germany)
2005-2007
Kyushu University
2001
Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead complement-driven nephropathies. Here we describe discovery highly potent, reversible, selective small-molecule inhibitor factor B, serine protease that drives central amplification loop AP. Oral administration prevents KRN-induced arthritis in...
Glypican-3 (GPC3) is a membrane-associated glycoprotein that significantly upregulated in hepatocellular carcinomas (HCC) with minimal to no expression normal tissues. The differential of GPC3 between tumor and tissues provides an opportunity for targeted radiopharmaceutical therapy treat HCC, leading cause cancer-related deaths worldwide. <b>Methods</b>: DOTA-RYZ-GPC3 (RAYZ-8009) comprises novel macrocyclic peptide binder GPC3, linker, chelator can be complexed different radioisotopes....
The alternative pathway (AP) of the complement system is a key contributor to pathogenesis several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. serine protease factor B (FB) node in AP integral formation C3 C5 convertase. Despite prominent role FB AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we...
Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin could also effective for neuropathic pain. Herein, we describe the efficacy of selective antihyperalgesics in a model pain rats after oral administration.
525 Background: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein whose expression largely absent in normal tissues. Significant upregulation of GPC3 has been observed approximately 75% hepatocellular carcinomas (HCC), and associated with poor prognosis. The differential between tumor tissues provides an opportunity for targeted radiopharmaceutical therapy (RPT) to treat HCC, leading cause cancer-related deaths worldwide. Methods: RAYZ-8009 comprises novel macrocyclic peptide binder...
On the basis of pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at P3 have been explored to enhance target, bone marrow, tissue distribution. Several structures were identified with improved distribution toward marrow. The representative inhibitor 7 this series revealed in vivo reduction C-terminal telopeptide type I collagen rats and monkeys.
The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may dysregulated glaucoma. purpose demonstrate that sGC activator MGV354 lowers IOP a monkey model glaucoma could considered as possible new clinical drug candidate.Changes cGMP were assessed primary human trabecular meshwork (hNTM) cells binding studies conducted using full-length protein. Ocular safety tolerability, exposure, efficacy rabbit...
A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from target-family tailored library. Optimization of both the prime and nonprime site residues flanking central transition-state surrogate resulted in analogues with improved potency pharmacokinetic (PK) properties, culminating identification 4-hydroxy-3,5-substituted 31. This compound showed high vitro toward human excellent off-target selectivity, 60% oral...
Solvolysis reaction of methyl (4S,5S)-4-(4′-methoxyphenyl)-5-tosyloxy-2(E)-hexenoate 5 in water-saturated MeNO2 gave the 1,2-migration product, (4S,5S)-5-hydroxy-4-(4′-methoxyphenyl)-2-(E)-hexenoate 6 (55% yield), which was converted to (R)-(4′-methylphenyl)hexanoate 11 25% overall yield (5 steps). Treatment (R)-11 with MeLi tertiary alcohol congener 12, subjected dehydration afford (R)-(−)-curcumene 1. An introduction hydroxyl group at meta-position aromatic ring achieved based on...
Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological environment, heme group of sGC can be oxidized becoming unresponsive to NO leading loss ability catalyze production cGMP. Recently dysfunctional sGC/NO/cGMP pathway contributing elevated intraocular pressure glaucoma. Herein we describe discovery molecules specifically designed topical ocular administration, which activate...
Total synthesis of (S)-(+)-and (R)-(-)-curcudiols (2) was achieved based on the 1,2-aryl migration (4R,5R)-and (4S,5S)-4-aryl-5-tosyloxy-(2E)-hexenoates (9) derived from (4S,5S)-4-epoxy-(2E)hexenoates (3), respectively.The phenolic sesquiterpenes bisabolane family have been isolated many different natural sources. 1 Among them, (S)-(+)-curcuphenol (1) and (S)-(+)-curcudiol (2), marine sponge Epipolasis sp.strongly inhibit activity gastric H, K-ATPase, 2 while (R)-(-)-curcuphenol (1),...
The solvolysis reaction of (4,5)-anti-4-aryl-5-tosyloxy-2(E)-hexenoates 4a-k gave (4,5)-anti-4-aryl-5-hydroxy-2(E)-hexenoates 2a-k and (4,5)-anti-5-aryl-4-hydroxy-2(E)-hexenoates 5a-k along with the complete inversion. This 1,2-aryl migration was induced by treatment heating in water-saturated nitromethane. On basis substituent effect on aromatic ring, this is thought to proceed via sigma-bridged phenonium ion. product selectivity between found be subtly governed substitution pattern ring...
Abstract Introduction: Carbonic Anhydrase IX (CA9) is a zinc metalloenzyme that regulates the pH for cell growth. CA9 considered an attractive target and upregulated in variety of cancers, especially, 95% clear renal carcinoma (ccRCC) where there remains large clinical unmet need despite availability several newly approved medicines. PeptiDream has identified PD-32766, novel macrocyclic peptide, targeting can be labeled with radionuclides such as copper (64Cu) lutetium (177Lu), which enables...
e16131 Background: Glypican-3 (GPC3) is a membrane-associated heparan sulfate proteoglycan primarily involved in embryonic development, and barely detectable normal adult tissues. Significant upregulation of GPC3 protein hepatocellular carcinomas (HCC) has been observed multiple immunohistochemistry (IHC) studies with up to 75% positivity rate, associated poor prognosis. not expressed healthy or non-malignant liver tissue. Targeting could fulfill an unmet medical need for HCC, leading cause...
MGV354 was being developed as a novel ocular therapy for lowering of intraocular pressure, key modifiable risk factor glaucoma. is an activator soluble guanylate cyclase, enzyme known to be involved in the regulation IOP. has been shown robustly lower IOP over 24 h after single topical drop rabbit and monkey pharmacology models. However, failed produce similar results patients with hypertension or open-angle glaucoma.With objective explaining lack efficacy clinic, we attempted study whether...
e15113 Background: Ephrin type-A receptor 2 (EphA2) is a glycoprotein of the ephrin subfamily. EphA2 primarily involved in tissue patterning during embryonic development, and its expression levels are low or absent normal adult tissues. However, overexpression has been observed multiple malignant tumors such as bladder, cervical, ovarian, colorectal, lung esophageal cancers. In addition to being tumor biomarker, plays an active role survival, metastasis neo-angiogenesis, which can lead poor...