Protease inhibitors: current status and future prospects.

Invented are novel heterocyclic carboxamide compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis

Inhibitors of akt activity

Muscarine, imidazole, oxazole, and thiazole alkaloids

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-α converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs.

Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

Compounds, pharmaceuticals, kits and methods are provided for use with DPP-IV and other S9 proteases that comprise a compound comprising: 
wherein M is N or CR 4 ; Q 1 and Q 2 are each independently selected from the group consisting of CO, SO, SO 2 , and C═NR 9 ; and each L, X, R 1 , R 2 , and R 3 are as defined herein.

Dipeptidyl peptidase inhibitors

Novel tetrahydro-2H-isoindoles have been prepared and evaluated as inhibitors of the COX-2 isoenzyme. A 1,3-diaryl substitution on the central polycyclic ring system and absence of a sulfonyl moiety are the two structural features of this chemical series. A short and easy synthetic pathway produced several derivatives which were shown to be potent and selective COX-2 vs COX-1 inhibitors (IC50 = 0.6−100 nM for COX-2, 100−>1000 nM for COX-1). Structural modifications established that a bicyclic ring appended to the pyrrole nucleus and 4,4‘-difluoro substitution on the phenyl rings were optimal for high inhibitory potency. Activity was confirmed in the human whole blood assay and subsequently in the murine air-pouch model in which in vivo PGE2 inhibitory activity was evaluated with respect to gastric tolerance (ED50 for inhibition of exudate PGE2 of 3 mg/kg and gastric PGE2 of 20 mg/kg). Gastric tolerance was further assessed after administration to mice of high doses (up to 400 mg/kg) of the inhibitors by m...

1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives: a new series of potent and selective COX-2 inhibitors in which a sulfonyl group is not a structural requisite.

Stereoselective synthesis of a new perhydroindole derivative of chiral iminodiacid, a potent inhibitor of angiotensin converting enzyme

Alpha amino acid derivatives (I), their optical isomers and addition salts, are new. Alpha amino acid derivatives of formula (I), their optical isomers and addition salts, are new: A = five-membered heterocycle, optionally substituted by a cyano group; Ak = 1-6C alkylene; X = single bond or phenylene; R1, R2, R4 = H or 1-6C alkyl; Y = NR4 or CH-NO2; R3 = NO2 or CN; and provided that: (i) when Y is CH-NO2, then R3 may further be 1-6C alkyl; and (ii) when A is unsubstituted, then Ak is propylene, X is a bond, Y is NH and R3 is NO2, are excluded.

Alpha-amino acid derivatives, method for their preparation and their use as dipeptidyl-peptidase IV inhibitors (DPP IV)

L'invention concerne les derives de formule generale (I): The invention relates to the derivatives of general formula (I): dans laquelle: in which: A represente avec les atomes de carbone et d'azote avec lesquels il est lie un groupement cycloamidique, tel que defini dans la description, A represents, with the carbon and nitrogen atoms to which it is bonded a cycloamidique group, as defined in the description, B represente avec les atomes d'azote et de carbone avec lesquels il est lie une structure polycyclique saturee telle que definie dans la description, B represents, with the nitrogen and carbon atoms to which it is attached a saturated polycyclic structure as defined in the description, R represente un atome d'hydrogene, un groupement alkyle inferieur eventuellement substitue, un groupement (imidazol-4-yl) methyle eventuellement substitue, un groupement (pyrazol-3-yl) methyle, un groupement (pyridin-2-yl) methyle eventuellement substitue, R represents a hydrogen atom, an optionally substituted lower alkyl group, an (imidazol-4-yl) methyl optionally substituted, a (pyrazol-3-yl) methyl, a (pyridin-2-yl) methyl optionally substituted leurs enantiomeres, diastereoisomeres et epimeres ainsi que leurs sels d'addition a un acide pharmaceutiquement acceptable. their enantiomers, diastereoisomers and epimers and also their addition salts with a pharmaceutically acceptable acid. Medicaments. Drugs.

Trh derivatives, their preparations and pharmaceutical compositions containing them

Perindopril, a powerful ACE inhibitor contains 5 chiral carbons, thus there is the possibility of 2(5) = 32 stereoisomers for the general structure 1. These 32 stereoisomers were synthesized by cross-coupling the 8 stereoisomers of perhydroindole 2-carboxylic acid benzylester with the 4 stereoisomers of 2-(1-carbethoxybutylamino) propionic acid 4, then hydrogenating the resulting benzylesters. Each stereoisomer of perindopril furnished by saponification the corresponding diacid stereoisomer 2 of perindoprilate which is the active form of perindopril. For each of the 32 stereoisomers 2 the in vitro ACE inhibitory potency (IC50) was determined. Four of them, including perindoprilate, had activities in the nanomolar range, and four more were ca. 10 x less active. The four acid esters 1 corresponding respectively to the four most active diacids 2 in vitro were studied (1 mg/kg via the oral route) for their in vivo activity in dogs. It could be concluded that p.o. absorption of the active acid esters 1 and their activation to the active diacid 2 depended only on the chiralities of the two ring junction carbons of the perhydroindole ring.

Bernard Portevin

Papers

1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives: a new series of potent and selective COX-2 inhibitors in which a sulfonyl group is not a structural requisite.

Stereoselective synthesis of a new perhydroindole derivative of chiral iminodiacid, a potent inhibitor of angiotensin converting enzyme

Alpha-amino acid derivatives, method for their preparation and their use as dipeptidyl-peptidase IV inhibitors (DPP IV)

Trh derivatives, their preparations and pharmaceutical compositions containing them

Synthesis and ACE inhibitory activity of the stereoisomers of perindopril (S 9490) and perindoprilate (S 9780).