Preclinicalclinical Pipeline

New treatments in development for onychomycosis are listed in Table 2. Currently, most treatments that are in clinical trials represent re-formulations of known an-tifungal agents combined with penetration enhancers in an effort to increase penetration through the nail plate. There are two treatments in clinical trials that contain novel antifungal agents. The first, in Phase 2, is a topical treatment that generates nitric oxide. The second, in Phase 3, is a topical treatment containing...

Constitutive Gpcr Activation Disease And Inverse Agonist Utility

There exists a growing literature on constitutive activation of GPCRs, and the reader is referred to several recent reviews on the topic 12,26,38 . It is important to distinguish GPCR systems that are persistently activated as a consequence of mutation, termed a constitutively active GPCR mutant from that of a wild type GPCR system that displays a high level of constitutive activity. Both types of systems are relevant for the utility of inverse agonists assuming the need to tone down the...

Pyrazole CB1 antagonists

The first cannabinoid receptor antagonist, rimonabant was described in 1994 by researchers at Sanofi 8,9 . Rimonabant belongs to a chemical family distinct from previously known cannabinoid ligands 1,5-diarylpyrazoles. Interestingly, most early attempts to identify a cannabinoid antagonist based on the structure of agonists such as classical cannabinoids (THC like compounds) or amino-alkyl indoles proved rather disappointing 10 . Several groups have recently described SR141716 analogues,...

Fosfluconazole Antifungal [4750

Fosfluconazole is a phosphate prodrug of fluconazole, and it was launched last year in Japan as an intravenous injection for the treatment of candidiasis and cryptococcosis infections. Fluconazole, a triazole antifungal agent, is a selective inhibitor of fungal cytochrome P450 sterol C-14 alpha-demethylation, and it is widely used for the treatment of patients with serious systemic fungal infections. Fluconazole is marketed in both oral and intravenous formulations, the latter being a dilute...

Pemetrexed Anticancer [7577

Introduction Introduced by Trade Name CAS Registry Pemetrexed, a pyrrolo 2,3-d pyrimidine-based antifolate that disrupts cell replication by inhibiting multiple folate-dependent metabolic processes, was initially developed and launched in the US for the treatment of malignant pleural mesothelioma in conjunction with cisplatin. Patients who are not candidates for surgery may benefit from this combination therapy. Clinical data demonstrated that the median overall survival time increased to 12.1...

Azacitidine Anticancer [913

Azacitidine is an antineoplastic agent launched last year for the treatment of myelodysplastic syndrome (MDS). MDS is a group of closely related diseases caused by abnormal blood-forming stem cells of the bone marrow. They are characterized by a hyperproliferative bone marrow, the presence of clonal blood cells with impaired morphology and maturation, and peripheral blood cytopenias resulting from ineffective blood cell production. The initial stem cell injury can be from cytotoxic...

Natalizumab Multiple Sclerosis [6874

Molecular Weight Expression system Recombinant humanized, murine monoelonal antibody Humanized IgG4K, anti-VLA4 149 kDa The a4 family of integrins expressed on the surface of leukocytes are involved in cell adhesion processes. The a4 integrin can pair with either of two p subunits to generate a heterodimeric cell surface receptor known as a4pl (VLA4) or a4p7. Ligands for VLA4 include vascular cell adhesion molecule-l (VCAM-l), which is expressed on activated vascular endothelium, while a4p7...

Clinically Studied Inhibitors 31 5LO and FLAP inhibitors

Reduce Corneum

Zileuton (1) is the only marketed 5-LO inhibitor and is approved for the treatment of asthma 44 . The treatment of mild asthmatics with zileuton (600 mg qid, 2 weeks) resulted in a 96 increase in plasma thromboxane B2 from baseline levels and a corresponding 62 increase in spontaneous platelet aggregation, suggesting a shunting of arachidonic acid metabolism to the cyclooxygenase pathway 45 . In a small clinical trial, zileuton provided a magnitude of prophylaxis in exercise-induced asthma (as...

Liverselective glucocorticoid receptor antagonists

The correlation between elevated hepatic glucose output and fasting hyperglycemia in type 2 diabetic patients is well established. Also, the link between elevated glucocorticoids (GCs) and glucose control suggested the desirability of exploring glucocorticoid receptor antagonism as a potential therapy for T2D. However, the critical role played by GCs in the hypothalamic pituitary axis (HPA) and potential toxicity due to systemic GC antagonism, suggests that liver-selective glucocorticoid...

Topical Microbicides Under Development 51 Preclinical

Microbicides currently under pre-clinical development are Alkyl sulfates, tobacco-derived antibodies and fusion proteins (HIV, HSV, HPV), anti ICAM-1 antibodies, betacyclodextrin, the entry fusion inhibitors C85FL, K5-N, and OS(H), cyanovirin-N, lime juice, mandelic acid condensation polymer (SAMMA), MC1220 (lead compound in the dihydroxy alkyl benzyl oxopyrmimidine series), the vaginal defense enhancer MucoCept HIV, Novaflux proprietary product, and porphyrins (Table 1). Table 1. Microbicides...

Other Structural Types

Several instances exist where only one or two examples of a structural class have been the subject of recent noteworthy studies. The attachment of quinolones or naphthyridines to other antibacterial pharmacophores has been extended to a new type. MBX-251D 40 comprises a quinolone attached to a DNA polymerase Illc inhibitor. It was potent against all Gram positives tested except for strains having both gyrase and Pol Illc mutations, and it was efficacious by the i.v. route in mouse i.p....

HT2C receptor ligands

It is well established from the past decade that the potential uses for 5-HT2c ligands include anxiety, depression, obesity and cognitive dysfunction 55-59 . Since the initial report of the 5-HT2C knockout mouse 60 , the interest in selective ligands had been very high but, until recently, unrealized. It has only been in the last few years that truly selective ligands have been discovered and activity in animal models been reported. In the recent past there has been a great deal of interest in...

Ligands for peroxisomeproliferator activated receptors PPARs

Investigation of the family of nuclear receptors PPAR- a, p, and g remains a highly active area of research in the diabetes field and was recently reviewed 11 . Findings that several PPAR agonists cause cancer in mice and rats, prompted a recently imposed FDA requirement for two-year carcinogenicity evaluation of all PPAR modulators prior to dosing in patients longer than six months 12 . This is expected to delay the clinical study of several compounds. Most advanced are the PPAR-g agonists...

Talaporfin Sodium Anticancer [9195

Light Sciences Corp. Meiji Seika Kaisha Nippon Petrochem. Light Sciences Corp. Meiji Seika Kaisha In collaboration with Light Sciences Corp. and Meiji Seika Kaisha, Nippon Petrochemicals has developed and launched the injectable photosensitizer talaporfin sodium in Japan for the photodynamic therapy (PDT) of cancer. The initial approval is for the treatment of early stage lung cancer, but Light Sciences Corp. and its subsidiaries are also developing talaporfin sodium for other...

Belotecan Anticancer [1417

Country of Origin Originator First Introduction Introduced by Trade Name CAS Registry No Molecular Weight CKD Pharmaceuticals Camtobell 213819-48-8 469.97 hydrochloride Belotecan, a DNA topoisomerase I inhibitor, is an analog of camptothecin. It was launched last year in the Republic of Korea as an injectable formulation for the treatment of ovarian and small cell lung cancer. Although camptothecin exhibits potent antineoplastic activity in vitro, its clinical application is hampered by severe...