Roche compounds

Tab. 15.3 Median values for molecular weight, polar surface area, chemical complexity, and rotatable bond count for literature datasets and for a set of Roche compounds...

Figure 10.5 Predicted versus observed AUC/Dose for 68 Roche compounds [6].

We thank our coworkers in Molecular Modeling/Cheminformatics at Roche, Basel, for scientifically stimulating discussions and valuable contributions. The fruitful collaboration with colleagues from the Lead Generation, Medicinal Chemistry, Roche Compound Depository, Assay Development HTS departments and the Molecular Properties Group is gratefully acknowledged. 

To overcome the limitations of known DNA gyrase inhibitors, a new drug discovery project was inititated at Roche. Searching for novel inhibitors by screening the Roche compound library provided no suitable lead structures. 

Probably the most intriguing and controversial CNS-active azide derivative to be investigated is another Hoffman-La Roche compound Ro 15-4513 (233), an analogue of the benzodiazepine receptor antagonist flumazenil (Ro 15-1788) (232). Not surprisingly, this compound was initially... 

This drug or the Roche compound, Ro 4-4602, when administered concomitantly with DOPA, lowered the required anti-Parkinsonism dose of DOPA 6-10-fold. Thus, many of the severe peripheral side effects engendered by the usual massive does of DOPA, including emesis and orthostasis, are mitigated. 

Peters, J.-U., Schnider, P., Mattel, P and Kansy M. (2009) Pharmacological promiscuity dependence on compound properties and target specificity in a set of recent Roche compounds. ChemMedChem, 4, 680-686. 

Gotz R, P Friesel, K Roch, O Papke, M Ball, M, A Lis (1993) Polychlorinated-/ -dioxins PCDDs, dibenzofu-rans PCDFs, and other chlorinated compounds in the River Elbe results on bottom sediments and fresh sediments collected in sedimentation chambers. Chemosphere 27 105-111. 

Merck has recently utilised a furo[2,3-b]pyridine core (554) as a bioisosteric replacement for the pyrazole scaffold of rimonabant (382) [328]. The same basic pharmacophore, that of two halo-substituted aryl groups and a third hydrophobic motif proximal to a hydrogen-bond acceptor, can be witnessed in the benzodioxole-based compounds, such as (555), disclosed by Roche [329]. 

A recent patent application from Roche [352] described a 2-amino-benzothiazole series. Roche claimed that compound (605) exhibited an IC50 value of 0.73 uM at CBi, and showed in excess of 10-fold selectivity over the CB2 receptor. The compounds were described as being of potential use in the treatment of a range of diseases, including CNS and psychiatric disorders, type-2 diabetes, gastrointestinal diseases, cardiovascular disorders, infertility disorders, inflammation, cancer, atherosclerosis, cerebral vascular incidents and cranial trauma. 

Further, using a combination of X-ray crystallography and mass spectroscopy, Knox et al. [73] has firmly established a central role for Ser-130 in the inhibition of SHV-1 /1-lactamase (class A) by tazobactam. Many additional modifications (Table 3) were carried out on tazobactam with the aim of increasing inhibitory activity against AmpC enzymes, but none of these derivatives (e.g., 13c, 13d, and 13e) had any advantage over tazobactam [74— 77]. Renewed interest in the modification at the C-2 position of sulbactam was developed when scientists from Hoffmann-La Roche disclosed a series of 2/J-alkenyl penam sulfones that possess the ability to simultaneously inactivate both class A penicillinase as well as class C cephalosporinase. Compound... 

For the syntheses of a large number of deoxypolypropionates requiring a,o -diheterofunctional intermediates, a couple of novel protocols, that are complementary with the conventional protocol using so-called Roche ester, have been developed (Scheme 33).199,200 More recently, the combined use of the ZACA reaction and the lipase-catalyzed kinetic resolution via selective acetylation has been shown to be practically attractive for the synthesis of enantio-merically pure compounds that cannot be readily purified by ordinary chromatography or recrystallization199,201 (Scheme 34). 

Enantioselective hydrogenation of />-kelo esters catalyzed by the modified Raney Ni is useful for the synthesis of biologically active compounds, as shown in Figure 32.15 [56-58]. A large-scale synthesis of (-)-tetrahydroHpstatin (orlistat), a pancreatic lipase inhibitor (F. Hoffmann-La Roche AG), is carried out using this method [58]. 

Other modifications of the non-constrained PAF framework have led Hoffmann La Roche s group to develop a further series of antagonistic compounds. The two closely related tetramethylene derivatives, both designated Ro 19-3704 (4c), are the most efficient and inhibit PAF-induced rabbit platelet aggregation with an IC50 value of 3.0 and 0.4 /iM respectively [113]. 

Roche, O., Trube, G Zuegge, J., Pflimlin, P., Alanine, A. and Schneider, G. (2002) A virtual screening method for prediction of the HERG potassium channel liability of compound libraries. Chembiochem A European Journal of Chemical Biology, 3, 455-459. 

The neuramidase inhibitor oseltamivir phosphate was discovered by Gilead Sciences and developed by Roche Pharmaceuticals under the name of Tamiflu (Scheme 5.13) to be used as an orally active antiviral compound for prevention and treatment of influenza infections. Because of the recent emergence of the avian flu, the demand for Tamiflu has gained momentum. Two industrially feasible syntheses are known, starting from (—)-shikimic acid and (—)-quinic acid, respectively (Scheme 5.13) [45]. 

Presently on the U.S. market there are three compounds commonly considered as peripheral dilating hypotensive agents. These are hydralazine (I), placed on the market in 1953 by CIBA, diazoxide (II) from Schering in 1973 and sodium nitroprusside (III) made available by Roche in 1974. 

The commercially available CAT model, iDEA (see Sect. 21.3.4.3) has been evaluated in a few studies. In one study [20], Roche Ltd. Supplied eight compounds without any supplemented data. In vitro permeability (using Caco-2 cell monolayers) and solubility values were generated and the human Tabs were predicted and compared to clinical data. In this study, the predicted... 

Roche, O., Schneider, P., Zuegge, J., Cuba, W., and Kansy, M. Development of a virtual screening method for identification of Frequent Hitters in compound libraries./. Med. Chem. 2002, 45, 137-142. 

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