F. Somers

Recent advances in inducible cyclooxygenase (COX-2) inhibition

Cyclooxygenase is the key enzyme in the biosynthesis of prostanoids, biologically active substances that are involved in several physiological processes but also in pathological conditions such as inflammation. Since ten years now, it is well known that this enzyme exists under two forms: a constitutive (COX-1) and an inducible form (COX-2). Both enzymes are sensitive to inhibition by conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Observations that COX-1, involved in several homeostatic processes, played a housekeeping role while COX-2 expression was associated with inflammation and other pathologies such as cancer proliferation have led to the development of COX-2 selective inhibitors in order to reduce the classical side-effects, of which gastric irritation is the most common, associated with the use of conventional NSAIDs.

Study of the ring closure reaction of o-aminoarylsulfonamides with 1,1’-thiocarbonyldiimidazole

Abstract 1,1′-Thiocarbonyldiimidazole was used as a ring closure agent for o-aminoarylsulfonamides. Beside the formation of the expected 3-thioxo-2,3-dihydro-4H-1,2,4-arylthiadiazine 1,1-dioxide derivatives, a new kind of compound was also obtained, namely the 3-(imidazol-1-yl)-4H-1,2,4-arylthiadiazine 1,1-dioxides. The latter appeared to be good reaction intermediates. The use of 1,1′-thiocarbonyldiimidazole opens a new synthetic route to 3-alkylamino-4H-1,2,4-arylthiadiazine 1,1-dioxides, a heterocyclic ring system expressing important pharmacological properties. This work is the first study on the ring closure properties of this reagent.

Hydroxylated analogues of ATP-sensitive potassium channel openers belonging to the group of 6- and/or 7-substituted 3-Isopropylamino-4H-1,2,4- benzothiadiazine 1,1-dioxides: Toward an improvement in sulfonylurea receptor 1 selectivity and metabolism stability

Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.

Synthesis and structural studies of 3-alkylamino-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides: a new class of heterocyclic compounds with therapeutical promises

Abstract 3-Alkylamino-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide represents a new class of heterocyclic compounds expressing important pharmacological properties. According to the position of the CN double bond in the thiadiazine ring, this heterocyclic ring system may exist under three different tautomeric forms. By means of spectral and X-ray data collected from selected compounds, the most favourable tautomeric form adopted by 3-alkylamino-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides devoid of an alkyl substituent in the 2- or in the 4-position was determined. The present study giving new insights in the geometrical and conformational aspects of pyridothiadiazinedioxides is important considering the pharmacological potentialities of this class of heterocyclic compounds.

Effect on insulin release of compounds structurally related to the potassium‐channel opener 7‐chloro‐3‐isopropylamino‐4H‐1,2,4‐benzothiadiazine 1,1‐dioxide (BPDZ 73): introduction of heteroatoms on the 3‐alkylamino side chain of the benzothiadiazine 1,1‐dioxide ring

7‐Chloro‐3‐pyridyl(alkyl)amino‐4H‐1,2,4‐benzothiadiazine 1,1‐dioxides and 3‐alkylamino‐7‐chloro‐4H‐1,2,4‐benzothiadiazine 1,1‐dioxides containing one or more heteroatoms on the side chain in the 3 position have been synthesized in an attempt to discover new potent KATP‐channel openers. The compounds were tested as putative pancreatic B‐cells KATP channel openers by measuring their inhibitory activity on the insulin releasing process. The influence on the biological activity of the nature of the side chain in the 3 position is discussed.

1,4,2-Benzo/pyridodithiazine 1,1-Dioxides Structurally Related to the ATP-Sensitive Potassium Channel Openers 1,2,4-Benzo/pyridothiadiazine 1,1-Dioxides Exert a Myorelaxant Activity Linked to a Distinct Mechanism of Action

The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-dioxides and 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides is described. Their biological activities on pancreatic β-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The aim was to assess the impact on biological activities of the replacement of the 1,2,4-thiadiazine ring by an isosteric 1,4,2-dithiazine ring. Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity. Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers. Tightly related 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a KATP channel activation and a calcium channel blocker mechanism. The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo- and pyridothiadiazine dioxides, for activity on KATP channels.

2-alkyl-3-Alkylamino-2H-Benzo- and pyridothiadiazine 1,1-dioxides: from K+ATP channel openers to Ca++ channel blockers?

Abstract A series of 2-alkyl-3-alkylamino-2Hbenzo and 2-alkyl-3-alkylamino-2Hpyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides, structurally related to BPDZ 44 and BPDZ 73, two potent pancreatic Bcells K+ ATP channel openers, were synthesized and tested on rat pancreatic islets (endocrine tissue) as well as on rat aorta rings (vascular smooth muscle tissue). Alkylation of the 2-position led to double bond tautomerization and formation of compounds with a 2Hconformation. In contrast to the previously described pyridothiadiazine dioxides, such as BPDZ 44, and 7-chlorobenzothiadiazine dioxides, such as BPDZ 73, the 2-alkylsubstituted analogs were found to be poorly active on the insulin releasing process although most drugs exhibited a vasorelaxant activity. As a result, the new 2-alkylsubstituted pyridinic compounds expressed a selectivity profile (vascular smooth muscle tissue vs pancreatic tissue) opposite to that of their nonalkylsubstituted counterparts, i.e. BPDZ 44. Additional investigations revealed that, in contrast to their non 2-alkylsubstituted analogs, the most interesting 2-methylsubstituted derivatives did not express the pharmacological profile of classical K+ATP channel openers. The pharmacological results rather suggest that alkylation of the 2-position of the thiadiazine ring led to drugs that could act as Ca2+ channel blockers rather than as potassium channel openers.

Synthesis and Biological Effects of New 3‐Alkylamino‐4H‐1,2,4‐Benzothiadiazine 1,1‐Dioxides on Insulin‐secreting Cells

3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides with nitro, amino or acetylamino groups in the 7-position have been synthesized in an attempt to discover new tissue-selective KATP-channel openers. The compounds were tested as putative pancreatic β-cells KATP-channel openers by measuring their inhibitory activity on the insulin releasing process. The influence of the substituent in the 7-position on the acidic character (pKa) and on biological activity is discussed. The nitrobenzene derivatives were biologically active, but less so than the un-derivatized parent pyridothiadiazine dioxides.

7-Chloro-(R)-3-[1-(cyclohexyl)ethylamino]-4H-1,2,4-benzothiadiazine 1,1-dioxide and 7-chloro-(S)-3-[1-(cyclohexyl)ethylamino]-4H-1,2,4-benzothiadiazine 1,1-dioxide

3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides structurally related to diazoxide are expected to present a pharmacological profile of potassium-channel openers. The influence on biological activity of the absolute configuration of the title compounds, both C 15 H 20 ClN 3 O 2 S, is being studied. The crystallographic results confirm the enantiomeric characterization of each compound.

Comparison of the Effects of Nimesulide and Nimesulide‐L‐lysine on PGE2 Production by COX‐1 and COX‐2 and on Chondrocyte Metabolism In‐vitro

Nimesulide, a non-steroidal anti-inflammatory drug and one of a promising class of selective COX-2 inhibitors, has a very interesting therapeutic profile. Unfortunately, it is poorly soluble in water, which leads to important difficulties in the formulation of injectable solutions. This problem can also affect the bioavailability of nimesulide. To increase the aqueous solubility of the drug a nimesulide-L-lysine salt was synthesized in our laboratory; its aqueous solubility was greater than that of nimesulide (solubility in purified water 7.5 mg mL−1, and 0.01 mg mL-1, respectively). The aim of this study was to compare the anti-inflammatory profiles of nimesulide and nimesulide-L-lysine salt in a two-step in-vitro investigation. First, we evaluated the COX-2 selectivity of the drugs by a method using purified COX-1 and COX-2 enzymes. In a second step we evaluated the effects of the drugs on the production of prostaglandin E2 (PGE2) and proteoglycan by chondrocytes from man. The results obtained confirmed the COX-2 selectivity of the two compounds. Nimesulide-L-lysine had the same anti-inflammatory profile as nimesulide on chondrocyte cultures and better water solubility. Nimesulide-L-lysine should, therefore, be used to prepare injectable preparations and should ameliorate bioavailability after oral treatments.