Evolution of a series of peptidoleukotriene antagonists: synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles.

1,3,5-Substituted indoles and indazoles have been studied as receptor antagonists of the peptidoleukotrienes. The best of these compounds generally had a methyl group at the N1 position, a [(cyclopentyloxy)carbonyl]amino or 2-cyclopentylacetamido or N'-cyclopentylureido group at the C-5 position, and an arylsulfonyl amide group as part of the acidic chain at the C-3 position of the ring. Such compounds had in vitro dissociation constants (KB) in the range 10(-9) - 10(-11) M on guinea pig trachea against LTE4 as agonist and inhibition constants (Ki) less than or equal to 10(-9) M on guinea pig parenchymal membranes against [3H]LTD4. A number of compounds were orally effective at doses less than or equal to 1 mg/kg in blocking LTD4-induced "dyspnea" in guinea pigs. Compound 45 [N-[4-[[5-[[(cyclopentyloxy)carbonyl]-amino]-1-methylindol-3- yl]methyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide, ICI 204,219; pKB = 9.67 +/- 0.13, Ki = 0.3 +/- 0.03 nM, po ED50 = 0.3 mg/kg] is currently under clinical investigation for asthma. In the indole series, certain alkylsulfonyl amides possessing a 3-cyanobenzyl substituent at the N-1 position (60, 61) were produced that had KB less than or equal to 10(-9) M on guinea pig trachea.

A novel potent non-benzodiazepine anxioselective agent with reduced dependence liability: ICI 198, 256.

ICI 198,256, a member of the cinnoline series, was shown to be a potent anxiolytic agent in several species of animals. In addition, ICI 198,256 exhibited potent activity as an antagonist of both metrazole and bicuculline-induced convulsions. The salient features of ICI 198,256 are that it possesses minimal sedative liability, lower ethanol interaction and possibly lower dependence liability than benzodiazepines (e.g., diazepam). Neurochemically, this structurally novel anxiolytic compound is potent and selective for the Type 1 (cerebellar) BZ receptors in vivo as well as ex vivo, and in addition shows an agonist BZ-like profile in a variety of systems. Thus, ICI 198,256 may offer several significant advantages in the treatment of anxiety in humans than existing benzodiazepines.

A new method for calculating the accretion rate of bone calcium and some observations on the suitability of strontium-85 as a tracer for bone calcium.

1. A new method for calculating the accretion rate (A) of bone calcium is proposed, based on an impulse analysis of 47Ca data. The method is free of most of the assumptions inherent in previous methods of analysis and appears to give more accurate estimates. 2. In fourteen normal subjects and twelve patients with metabolic bone disease, measurements of A by the new method gave very similar results to the mineralization rate calculated by the method of Burkinshaw et al. (1969). Analysis of twelve studies performed by Neer et al. (1967) gave good agreement with their five compartment model. A close relation between A and Marshall's (1964) A5 was observed, but the latter gave systematically higher results. 3. In sixteen studies both 47Ca and 85Sr were injected simultaneously. Although there were no systematic differences between the values of A for the two tracers, the differences between individual values were greater than the known experimental errors.

Antiviral effects of aphidicolin, a new antibiotic produced by Cephalosporium aphidicola.

Aphidicolin is an antibiotic of novel structure produced by the mold Cephalosporium aphidicola. It is a potent inhibitor of cellular deoxyribonucleic acid synthesis, and it also strongly inhibits the growth of herpes simplex virus both in tissue culture and in the rabbit eye. Aphidicolin is active against iododeoxyuridine-resistant herpes virus, and does not itself readily induce the formation of drug-resistant strains of herpesvirus.