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The synthesis of a series of RGD mimetic alpha(v)beta3 antagonists containing a hydantoin scaffold is shown. The results demonstrate some of the structural requirements for the design of selective alpha(v)beta3 antagonists (vs alpha(IIb)beta3) in terms of the Arg-mimetic, the distance between N- and C-terminus and the lipophilic side chain.

2-[(2-Pyridylmethyl)sulfinyl]thienoimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K(+)-ATPase. The [3,4-d] isomers of the two possible thienoimidazole series were found to be potent inhibitors of gastric acid secretion in vitro and in vivo. Structure-activity relationships indicate that especially lipophilic alkoxy, benzyloxy, and phenoxy substituents with additional electron-demanding properties in the 4-position of the pyridine moiety combined with an unsubstituted thieno[3,4-d]imidazole lead to highly active compounds with a favorable chemical stability. Various substitution patterns in the thieno[3,4-d]imidazole moiety result in lower biological activity. The heptafluorobutyloxy derivative saviprazole (HOE 731, 5d) was selected for further development and is currently undergoing clinical evaluation. Comprehensive pharmacological studies indicate a pharmacodynamic profile different to omeprazole, the first H+/K(+)-ATPase blocker introduced on the market.

Saviprazole (HOE 731), a substituted thienoimidazole, caused a dose-dependent inhibition of gastric acid secretion in dogs and rats with ID50 values which were not significantly different from that of omeprazole indicating that both compounds are equally effective. The duration of action in dogs lasted for more than 24 h and was dependent on the state of stimulation. Measurement of serum concentrations of 1 mg/kg saviprazole after intravenous or intraduodenal administration revealed a bioavailability of about 60% in dogs. The elimination half-life was about 30 min following both routes of administration. In rats basal acid secretion was inhibited by saviprazole. In addition stimulation of acid secretion by histamine, desglugastrin, carbachol and isobutylmethylxanthine-forskolin was equally inhibited. This was in agreement with the known mechanism of action, inhibition of the gastric proton pump which is the last step of acid secretion within the parietal cell. Surprisingly, at high dose levels, saviprazole differed from omeprazole. After saviprazole, 1 mg/kg i.v. to dogs, acid output dropped to zero but recovered within 30 min to a level of 90%, whereas omeprazole depressed acid output completely over the whole observation period (4.5 h). Similar results were obtained in pylorus-ligated rats.

HOE 731, a substituted thienoimidazole derivative, was studied on [14C] aminopyrine uptake and oxygen consumption in isolated rabbit gastric glands. HOE 731 caused a concentration-dependent inhibition of [14C]aminopyrine uptake during histamine and dbcAMP stimulation. The inhibition during dbcAMP stimulation was in accordance with its proton-pump inhibiting properties, which has already been reported. (Herling et al., Gastroenterology 96: A206, 1989). IC50 values were during histamine stimulation 0.8 +/- 0.3 microM and during dbcAMP stimulation 1.3 +/- 0.4 microM. The inhibition was reversible after addition of dithioerythritol and was of a non-competitive type. Omeprazole caused similar inhibitory effects in the same concentration-range. During time-course studies in glands, the inhibitory effect on [14C]aminopyrine uptake of 0.1 microM HOE 731 already appeared after 10 min of incubation but decreased with increasing incubation time, while 0.1 microM omeprazole caused an unchanged inhibition which started after 30 min of incubation. The concentration of 3 microM of HOE 731 and omeprazole caused a comparable constant inhibition. After pre-incubation for 135 min under basal conditions with subsequent stimulation of the glands with dbcAMP, the inhibitory effect of 10 microM HOE 731 also decreased in contrast to omeprazole. During stimulation for 4 hr, the inhibition of both compounds remained constant. In oxygen consumption studies HOE 731, at 100 microM, caused a strong inhibition down to basal values. This inhibitory effect could be prevented totally when 10 mM imidazole was added to neutralize the acidic compartment of the parietal cell during stimulation. It is concluded that HOE 731 needs acid-activation like omeprazole to inhibit the proton pump, but probably due to its chemical differences (stability, pH for conversion of HOE 731 to its active form) it shows a different inhibitory profile (faster transformation into its active moiety with faster onset of a partially reversible inhibition) as compared to omeprazole.

A series of carboxyalkylthio-substituted thiazole-carboxylic acids was synthesized and examined for macrophage activation and stimulation of the DTH (delayed type of hypersensitivity)-reaction. The structure-activity relationship in this series of new immunomodulators is discussed. Broadest immunological activity was seen for [2-(3-carboxy-1-propylthio)-4-methyl-1,3-thiazole]acetic acid (tiprotimod, HBW 538) which was selected for further studies.

7-[2-(2-Aminothiazol-4-yl)-2-(Z)-oxyiminoacetamido]-3-[(s ubs tituted-1-pyridinio)methyl]ceph-3-em-4-carboxylates II are a group of beta-lactam antibiotics with extraordinary high antibacterial activity. The promising member of this group, cefpirome (HR 810, II-1) is a candidate for clinical use. Synthetic pathways to II starting from cefotaxime derivatives I or 7-aminocephalosporanic acid (7-ACA) are described. A preferred method for the conversion of I to II or 7-ACA to precursors III respectively employs iodotrimethylsilane and an excess of the pyridine base. Structure-activity studies reveal an optimum overall activity in the series of pyridines with fused saturated and unsaturated rings or cyclopropyl- and alkoxy substituents. Favorable oxyimino substituents are methyl, ethyl, difluoromethyl and carbamoylmethyl groups. Acidic substituents lead to decreased activity against Staphylococcus aureus SG 511. Introduction of halogen in the thiazole nucleus causes improvement of activity against the K1 beta-lactamase producing Klebsiella aerogenes 1082 E strain.

S 3337, 2-(2-ethylaminobenzylsulfinyl)-5,6-dimethoxybenzimidazole, and S 1924, 2-(5-methyl-2-picolylsulfinyl)-1H-thieno[3.4-d]imidazole, are members of new classes of H+, K+-ATPase inhibitors. Their effects on H+, K+-ATPase and 14C-aminopyrine uptake in gastric glands were studied as well as in vivo in pylorus-ligated rats, stomach-lumen-perfused rats and Heidenhain pouch dogs. Their inhibitory effects were compared with the effect of omeprazole. In pylorus-ligated rats the two compounds showed a similar effectiveness as omeprazole. In stomach-lumen-perfused rats and in particular in Heidenhain pouch dogs, S 3337 was clearly less effective than omeprazole, while S 1924 was similarly effective in all in vivo models and in the H+, K+-ATPase assay as omeprazole. The difference in potency between S 1924 and omeprazole on 14C-aminopyrine uptake in gastric glands can be explained by the lower pKa value of S 1924 (3.4) than that of omeprazole (4.0). Additionally, this study shows that there was no correlation between the effects in rats, particularly in pylorus-ligated rats, and in dogs for the H+, K+-ATPase inhibitors tested. It is concluded from this study that substituted thieno[3.4-d]imidazoles represent a new class of potent gastric acid inhibitors.

The synthesis as well as in vitro antibacterial activity and pharmacokinetic behavior of cefodizime (HR 221, 1a), its analogs and derivatives is described. In this comparison, cefodizime stands out for its balance between its high antibacterial activity, prolonged elimination half-life and high AUC in mice and dogs.

The synthesis and antibacterial activity in vitro of 7-(2-heteroarylacetamido)-3-[(2,3- cyclopentenopyridinium)methyl]cephalosporins and of some related compounds with different ammonium functions in 3'-position are described. The 7-[5-amino-1,2,4-thiadiazol-3-yl] and the 7-[4-aminopyrimidin-2-yl] analogues of cefpirome and compounds with 3-aliphatic ammoniummethyl functions have excellent antibacterial activity. Cephalosporins with different N-heterocycles other than pyridine in 3'-position are less active than their 3-pyridiniummethyl analogues. Attachment of a pyridinium group to a cephem at C-3 via a thiomethyl or an aminomethyl bridge causes reduction of antibacterial activity.