Structure-activity relationships of selective estrogen receptor modulators: modifications to the 2-arylbenzothiophene core of raloxifene.

The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.

The synthesis and biological evaluation of 7 beta-[2-(2-aminooxazol-4-yl)-2-Z-methoximinoacetamido]-cep halosporin antibiotics.

7 beta-[2-(2-Aminooxazol-4-yl)-2-Z-methoximinoacetamido]-3-cep hem -4-carboxylic acids 12 and 13 were synthesized. The microbiological activity of 12 and 13 as well as the beta-lactamase stability of 12 were discussed. Both 12 and 13 were quite active against a wide variety of microorganisms although usually less active than cefotaxime.

The synthesis and biological evaluation of 7 beta-[2-(5-amino-[1,2,4] oxadiazol-3-yl)-2-Z-methoximinoacetamido]-cephalosporin derivatives.

A series of 7 beta-[2-(5-aminooxadiazol-3-yl)-2-Z-methoximinoacetamido] -3-cephem-4-carboxylic acids (7a-g) were synthesized and evaluated microbiologically Although somewhat less active than cefotaxime 7a-g showed good antimicrobial activity against a wide variety of Gram-positive and Gram-negative bacteria. The beta-lactamase stability of 7a and 7f was also discussed.

Bis-trimethylsilylcefamandole: an unusually stable trimethylsilyl-intermediate.

The preparation of crystalline bis-trimethylsilylcefamandole (7) and its utility in the preparation and purification of cefamandole are described. Although stable to solvolysis in isopropyl alcohol, 7 underwent smooth conversion to cefamandole in the presence of water, methanol, or ethanol.

Orally active esters of cephalosporin antibiotics. II. Synthesis and biological properties of the acetoxymethyl ester of cefamandole.

The synthesis of the acetoxymethyl (AOM) ester of cefamandole (CM) is described. The sparingly soluble ester is shown to be well absorbed orally by mice, but only when administered in solution in a partially non-aqueous vehicle, 50% propylene glycol. Neither the ester in aqueous suspension nor the sodium salt of CM in solution is well absorbed orally. The rate of oral absorption of the ester from solution is very rapid as shown by the early peak time and shape of the plasma level curve. Oral bioavailability from solution is at least 60% and is apparently limited only by hydrolysis or precipitation of a variable portion of the ester dose in the intestinal lumen prior to absorption.