Werner Rittel

Oxazolidinones, a new class of synthetic antituberculosis agent. In vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis.

DL-S-n-(3-(4-acetyl)-2-oxo-5-oxazolidynyl methyl) acetamide (DuP-721) is an orally active representative of the oxazolidinone series of antimicrobials. At concentrations ranging from 1.5 to 4 micrograms/ml, DuP-721 inhibited equally the strains of Mycobacterium tuberculosis susceptible and resistant to conventional antituberculosis drugs. DuP-721 inhibited M. gordonae and M. fortuitum at 3.9 micrograms/ml, M. kansasii at 1.95, and M. scrofulaceum at 15.6 micrograms/ml. It was not active against M. avium and M. intracellulare at concentrations of 250 micrograms/ml. The inhibition of the metabolism of M. tuberculosis as indicated by the liquid scintillation radiometric method was 56% at fourfold the minimum inhibitory concentration (MIC) of DuP-721 that compared well to that of the fourfold MIC concentrations of rifampicin and isoniazid. The in vitro activity of DuP-721 was not affected by reducing the pH from 6.8 to 5.5. In mice infected with M. tuberculosis, the 50% effective dose (ED50) for DuP-721 was 13.2 mg/kg when administered daily beginning 4 hr postinfection for 17 days. The ED50 was 71.8 mg/kg when DuP-721 was administered only on days 11 and 12 postinfection. A 100% survival rate was obtained at 50 and 160 mg/kg when DuP-721 was administered daily for 17 days, and only on days 11 and 12 after the infection, respectively. The increase in the survival time by DuP-721 at 100 mg/kg (eightfold the ED50 dose) when administered daily for 17 days beginning 4 hr after infection was inferior to that by eightfold the ED50 dose of rifampicin and isoniazid administered on days 11 and 12 postinfection.(ABSTRACT TRUNCATED AT 250 WORDS)

[Structure-activity relationship of human calcitonin. III. Biological activity of synthetic analogues with shortened or terminally modified peptide chains (author's transl)].

Assays of 8 synthetic analogues of human calcitonin in rats showed that their hypocalcaemic activity was drastically reduced by deletion of the C-terminal amide group, chain-shortening or opening of the disulphide ring, but unaffected or enhanced by modification of the N-terminal amino group.Assays of 8 synthetic analogues of human calcitonin in rats showed that their hypocalcaemic activity was drastically reduced by deletion of the C-terminal amide group, chain-shortening or opening of the disulphide ring, but unaffected or enhanced by modification of the N-terminal amino group.

ANALOGUES OF HUMAN CALCITONIN: IV. INFLUENCE OF LEUCINE SUBSTITUTIOS IN POSITIONS 12, 16 AND 19 ON HYPOCALCAEMIC ACTIVITY IN THE RAT

The replacement of the three aromatic amino acids in positions 12, 16 and 19 of human calcitonin (HCT) leucine residues, which occupy the corresponding positions in ultimobranchial, e.g. salmon and eel, calcitonins, increased the hypocalcaemic potency of the peptide, as determined by bioassay on the rat, about 10‐fold. The individual substitutions were not all equally augmentative: leucine (12) enhanced the activity of HCT about 4‐5 times, but leucine (16) and (19) afforded no increase at all. Combination of leucine (12) with a deamino cysteine at the N‐terminmus yielded an analogue 10 times more potnet than HCT. Another analogue containing valine in position 8 in place of methionine as well as the three leucine substituents in position 12, 16 and 19 proved more active than the tri‐leucine analogue, but the additional introduction of tyrosine (22) nearly doubled the hypocalcaemic potency of the latter. The duration of the hypocalcaemic effects of the substituted peptides closely followed the changes in potency.

Analogues of human calcitonin I. Influence of modifications in amino acid positions 29 and 31 on hypocalcaemic activity in the rat

The principal sites of calcitonin biosynthesis are the C-cells of the thyroid gland in mammals and the ultimobranchial body in birds, reptiles and fish. The amino acid sequences of the thyrogenic calcitonins from four species are known and two, the human [l] and the porcine [2] hormones, have been synthesized [3,4,5]. Attempts to elucidate the sequence of and synthesize ultimobranchial peptides, on the other hand, have up to now only succeeded in the case of salmon calcitonin [6,7], though others have been isolated in highly purified form. The calcitonins so far obtained from ultimobranchial glands exhibit greater biological activity in rat assays than dhose of thyroid origin [8]. This must be attributable to some particular amino acids, since the sequential differences between the thyroid hormones, which are all roughly equal in activity, are as great or even greater than the differences between them and the ultimobranchial peptides.