Design, synthesis, and physicochemical properties of a novel, conformationally restricted 2,3-dihydro-1,3,4-thiadiazole-containing angiotensin converting enzyme inhibitor which is preferentially eliminated by the biliary route in rats.

Two novel series of dihydrothiadiazole ring containing inhibitors of angiotensin converting enzyme have been designed and synthesized. The compounds are highly potent enzyme inhibitors and, as a consequence of conformational restriction, chemically stable with respect to undesirable cyclization reactions. The most interesting compound from this series, 5a (FPL 63547), is the monoethyl ester prodrug of the highly potent "aminocarboxy" inhibitor 5b (FPL 63674). It produces an antihypertensive effect of long duration in animal models after oral dosing. Unlike other ACE inhibitors, 5b is eliminated almost entirely by biliary clearance in the rat. The favorable pharmacological properties of 5a and 5b are rationalized in terms of their unique physicochemical profiles. The clear preference for biliary clearance seen with 5b is consistent with its lipophilicity and its high degree of net ionization at physiological pH, which results from the very low pKa of the C-terminus carboxylic acid function. FPL 63547 is presently undergoing clinical investigation in man.

Lipophilicity of zwitterionic sulphate conjugates of tiaramide, propranolol and 4'-hydroxypropranolol.

1. Metabolism of basic drugs may result in the formation of zwitterionic sulphate conjugates. The additional ionization introduced by the sulphate group into these compounds compared with the basic parent drug does not produce a corresponding increase in hydrophilic character. 2. Zwitterionic conjugates have constant lipophilicity between their pKa values. The opposite charges on the ionizing functional groups in this pH range appear to cancel the effect of each other on lipophilicity. 3. In the case of propranolol the O-sulphate derivative is more lipophilic than the parent compound at pH values below 7, despite the ionized character of the sulphate function. 4. The decrease in lipophilicity appears to be related to the separation in the molecular structure of the amino and sulphate groups.

Predictive structure-activity relationships in a series of pyranoquinoline derivatives. A new primate model for the identification of antiallergic activity.

A new primate model has been developed for the evaluation of antiallergic agents. Compounds are tested for their ability to inhibit anti-IgE induced histamine release from the bronchoalveolar mast cells lavaged from the lungs of Macaca arctoides infected with the parasite Ascaris suum. A number of 6-substituted pyranoquinoline derivatives have been evaluated and the activities were subjected to Hansch analysis. A highly significant correlation with lipophilicity (pi) and Hammett sigma p values was obtained. The relationship was used to predict further compounds for synthesis giving rise to new, potent analogues. Some apparently anomalous results could be explained by differences in the ionization of, or tautomerism in, the quinoline ring.

Distribution coefficient, a convenient term for the relation of predictable physico-chemical properties to metabolic processes.

1. The consequences of metabolic transformation on lipophilicity have been considered using the terms log P (partition coefficient) and log D (distribution coefficient). 2. Transformations which result in no change in the degree of ionisation can be readily predicted by the use of fragmental constants and log P. 3. If metabolism alters the degree of ionization then the distribution coefficient, log D, at physiological pH is a more appropriate term to use. Intuitive empirical observations may be incorrect and lead to false assumptions about the lipophilicity or water solubility of metabolites. 4. Metabolism may form zwitterionic molecules. These metabolites need special consideration since their penetration into lipid phases may be greater than expected.

Gastrointestinal absorption of the strongly acidic drug proxicromil.

Gastrointestinal absorption of the strongly acidic drug proxicromil has been studied with respect to its physical organic chemistry. The lipophilicity of the drug above pH 6 in octanol-buffer partition experiments is dependent on ion pair formation. Similar trends were demonstrated for the in vitro partition of the compound into GI tissue. The absorption of the compound from the perfused GI tract of rats in vivo was not consistent with classical un-ionized drug absorption theories and indicated the operation of other processes, especially ion pair formation, as major mechanisms of proxicromil absorption.

Isolation and identification of the fluorescent degradation product of some beta-lactam antibiotics.

A fluorescent degradation product of cephalexin, recently employed in the determination of this antibiotic in aqueous solution and human plasma, has been isolated and identified as 2-hydroxy-3-phenyl-6-methylpyrazine. Spectroscopically and chromatographically the product is indistinguishable from that obtained by the same method from a series of other cephalosporins and penicillins bearing an alpha-amino group on the side-chain, and from the pyrazine structure produced by synthesis. Two reported methods for the fluorimetric determination of ampicillin have also been found to yield the same degradation product and not the suggested diketopiperazine structure.