Inhibitors sulfonamides

Folic acid synthesis inhibitors Sulfonamides Trimethoprim... 

Orally administered carbonic anhydrase inhibitors lower the intraocular pressure of glaucoma patients, however they induce a number of intolerable side effects associated with extraocular inhibition of the enzyme [5,6]. Thus, much research has been directed towards the search for a topically effective agent. Several compounds have been synthesized since the 1980 s in Merck Sharp Dohme Research Laboratories, and have been found to be topically active in man [7]. Unfortunately, many of these compounds were not very soluble. Attempts to obtain an active carbonic anhydrase inhibitor with good solubility resulted in the synthesis of Dorzolamide hydrochloride [8,9], which was first made available for pharmacological evaluation in 1987. Like other carbonic anhydrase inhibitors sulfonamides (such as acetazolamide, ethoxzolaniide, and methazolamide) dorzolamide is an inhibitor of human carbonic anhydrase isoenzymes I, II, and IV. In contrast to the other sulfonamides, dorzolamide is a potent inhibitor of isoenzymes II and IV, and a weak inhibitor of isoenzyme I [ 10]. Isoenzyme II is thought to play a major role in aqueous humor secretion. 

Chemical Class Carbonic anhydrase inhibitor sulfonamide derivative... 

Lu RJ, Tucker JA, Zinevitch T et al (2007) Design and synthesis of human immunodeficiency virus entry inhibitors sulfonamide as an isostere for the a-ketoamide group. J Med Chem 50 6535-6544... 

Thaisrivongs S, Skulnick HI, Turner SR. Structure-based design of HIV protease inhibitors sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones as nonpeptidic inhibitors. J Med Chem 1996 39 4349-4353. 

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

The sulfa dmgs are stiH important as antimicrobials, although they have been replaced in many systemic infections by the natural and semisynthetic antibiotics. They are of great value in third world countries where problems of storage and lack of medical personnel make appropriate use of antibiotics difficult. They are especially useful in urinary tract infections, particularly the combination of sulfamethoxazole with trimethoprim. Their effectiveness has been enhanced by co-adniinistration with dihydrofolate reductase inhibitors, and the combination of sulfamethoxazole with trimethoprim is of value in treatment of a number of specific microbial infections. The introduction of this combination (cotrimoxazole) in the late 1960s (1973 in the United States) resulted in increased use of sulfonamides. 

Sulfonamides in combination with dihydrofolate reductase inhibitors are of continuing value. Pyrimethamine [58-14-0] (5) in combination with sulfonamides is employed for toxoplasmosis (7), and a trimethoprim (6)-sulfamethoxa2ole preparation is used not only for urinary tract infections but also for bmceUosis, cholera, and malaria. 

Pharmacologically useful isoxazoles (B-82MI41600) include antibacterial sulfonamides (614), (615) and (616), semisynthetic penicillins (617), (618), (619) and (620), semisynthetic cephalosporin (621), anabolic steroid (622), the monoamine oxidase inhibitor (623) (used in psychotherapy), antiinflammatory agent (624) and antitumor agent (625). 

Thiazide diuretics have a venerable history as antihypertensive agents until the advent of the angiotensin-converting enzyme (ACE) inhibitors this class of drugs completely dominated first line therapy for hypertension. The size of thi.s market led until surprisingly recently to the syntheses of new sulfonamides related to the thiazides. Preparation of one of the last of these compounds starts by exhaustive reduction of the Diels-Alder adduct from cyclopentadiene and malei-mide (207). Nitrosation of the product (208), followed by reduction of the nitroso group of 209,... 

Partaledis JA, Yamaguchi K, Tisdale M, Blair EE, Falcione C, Maschera B, Myers RE, Pazhanisamy S, Futer O, CuHinan AB et al (1995) In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydrox-yethylamino sulfonamide inhibitors of HIV-1 aspartyl protease. J Virol 69 5228-5235 Patick AK (2006) Rhinovirus chemotherapy. Antiviral Res 71 391-396... 

Viader MP, McKeever BM, Navia MA. Thienothiopyran-2-sulfonamides novel topically active carbonic anhydrase inhibitors for the treatment of glaucoma. J Med Chem 1989 32 2510-13. 

In 1975, SAR studies involving actinonin investigated an analogue in which the orientation of the Pl -P2 amide bond was reversed (13), but the compound was found to lack antibacterial activity. Since then, however, descriptions of some /i-aminohydroxamic acids and /i-amino-A-formyl-A-hydroxylamines as PDF inhibitors have appeared in the patent literature. Patent applications from Senju [97] and De Novo [98] pharmaceuticals cover Pl -P2 amides (14), ureas (15, 16) and sulfonamides (17). 

Angiotensin converting enzyme inhibitors, azathioprine, mer-captopurine, mesalamine, sulfasalazine, sulfonamide antimicrobials, and tetracyclines... 

Local side effects include burning, stinging, itching, foreign body sensation, dry eyes, and conjunctivitis. Brinzolamide may have a lower incidence of these side effects since the drug is in a neutral pH solution. Dorzolamide has been reported to cause irreversible corneal decompensation. Taste abnormalities have been reported with each agent. Both topical carbonic anhydrase inhibitors are sulfonamides and are contraindicated in patients with history of sulfonamide hypersensitivity.10,13... 

Darunavir (DRV) 300 mg tablet DRV 600 mg + Use with caution in Should be given Skin rash (has a sulfonamide CYP3A4 inhibitor and... 

The ligand tris[2-(l-methylbenzimidazol-2-yl)ethyl] nitromethane (25) has been used in the formation of zinc complexes as models of the active site of carbonic anhydrase, and the formed complexes reveal affinity for the sulfonamide-containing enzyme inhibitor acetazolamide.248... 

Not all drugs contain functional groups that lend themselves readily to prodrug derivatization. A case in point is the carbonic anhydrase inhibitors such as acetazolamide, ethoxzolamide, and methazolamide. Although the amino functional group of their sulfonamide moiety can be methylated, the resulting analogs... 

Jones-Hertzog, D.K. Jorgensen, W.L., Binding affinities for sulfonamide inhibitors with human thrombin using Monte Carlo simulations with a linear response method, J. Med. Chem. 1997, 40, 1539-1549... 

D. K. Jones-Hertzog and W. K. Jorgensen, Binding affinities for sulfonamide inhibitors... 

COX-2 selectivity was evaluated in vitro by using the human whole blood assays of COX isoenzyme activity. Three compounds, not bearing the sulfonamide group present in valdecoxib, have been found to be selective COX-1 inhibitors. 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

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