Discovery of the hemifumarate and (alpha-L-alanyloxy)methyl ether as prodrugs of an antirheumatic oxindole: prodrugs for the enolic OH group.

Ether, ester, and carbonate derivatives of the antirheumatic oxindole 1 were prepared and screened as potential prodrugs of 1. This effort led to the discovery of the (alpha-L-alanyloxy)-methyl ether and hemifumarate derivatives of 1 which deliver the drug efficiently into the circulation of test animals, are stable in the solid state, and possess good stability in solution at low pH as required to ensure gastric stability. Success in achieving acceptable bioavailabilities of 1 across species (rats, dogs, and monkeys) followed the inclusion of ionizable functionality within the promoiety to compensate for masking the polar enolic OH group of the free drug. However, the introduction of ionizable functionality was often associated with decreased stability, as demonstrated by the hemisuccinate, hemiadipate, hemisuberate, and alpha-amino ester derivatives of 1 which could not be isolated. A clear exception was the hemifumarate derivative of 1 which was not only isolable but actually more stable at neutral pH than the nonionizable ester analogues. The solution and solid state stability of the hemifumarate, together with its activity as a prodrug of 1, suggests that hemifumarate be considered as an alternative to hemisuccinate as a prodrug derivative for alcohols, particularly in situations where solution state stability is an issue.

Pirbuterol, a selecttve beta2 adrenergic bronchodilator.

Pirbuterol, 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine, is a new beta2 adrenergic agonist bronchodilator. Comparison of the relative potencies of pirbuterol, salbutamol and isoproterenol as relaxants of isolated guinea-pig tracheal muscle and as positive chronotropic agents in isolated guinea-pig atria indicate that the relative selectivity of pirbuterol for pulmonary as opposed to cardiac tissue is 9 times greater than that for salbutamol and some 1500 times greater than that for isoproterenol. Pirbuterol is effective by the oral, intravenous and inhalation routes of administration. In conscious guinea pigs, pirbuterol antagonizes both histamine- and acetylcholine-induced bronchoconstriction and "microshock" anaphylaxis; combinations of pirbuterol and theophylline cause additive effects against histamine-induced bronchoconstriction. In conscious dogs, the cardiovascular effects of pirbuterol are clearly distinguished from those of salbutamol, in that salbutamol causes a more pronounced tachycardia. In anesthetized dogs the cardiovascular effects of pirbuterol and salbutamol are comparable; they are less potent than isoproterenol and have less pronounced although longer lasting effects.

CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterization.

CP-45,899 {3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 4,4-dioxide, [2S-(2alpha,5alpha)]} is an irreversible inhibitor of several bacterial penicillinases and cephalosporinases. In the presence of low concentrations of CP-45,899, ampicillin and other beta-lactams readily inhibit the growth of a variety of resistant bacteria that contain beta-lactamases. CP-45,899 used alone displays only weak antibacterial activity, with the notable exception of its potent effects on susceptible and resistant strains of Neisseria gonorrhoeae. CP-45,899 appears to be somewhat less potent but markedly more stable (in aqueous solution) than the recently described beta-lactamase inhibitor clavulanic acid. The spectrum extensions provided by the two compounds are similar. A 1:1 mixture of CP-45,899 and ampicillin displays marked antimicrobial activity in mice experimentally infected with ampicillin-resistant Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, and Proteus vulgaris.