N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent

3-?4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl?-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-?4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl?propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-?4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl? ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.     

Inhibitory action of YJA20379, a new proton pump inhibitor on Helicobacter pylori growth and urease

The use of an episiotomy for vaginal delivery is a controversial topic in modern obstetrics. If one is done, however, correct technique of perineal trauma repair is important. The usual episiotomy has traditionally been closed with interrupted suture. The use of a less reactive material, e.g. polyglycolic acid (Dexon), seem to be suitable for subcutaneous skin closure and beneficial in terms of acute postpartum discomfort and healing. The comparison of healing and patient comfort parameters between interrupted and subcutis polyglycolic acid suture used for episiotomy repair after delivery was done. Patients had follow-up during hospital stay, and two months after delivery a self administered questionnaire was sent to all women who participated, enquiring about perineal pain, resumption of sexual intercourse and cosmetics of suture line. Of 52 patients who had repair with interrupted suture, 21 were lost to follow-up. Of 65 gravidas who had repair with subcutis suture, 23 were lost to follow-up. At the 3rd day postpartum examination, patients with subcutis sutures had significantly better healing. An inflammatory process was present in 2 of 52 patients with interrupted sutures comparable with 1 of 65 in the subcutis group, and a gaping wound in 0 of 52 and 1 of 65, respectively. Recovery of function, measured by resumption of sexual activity by 8 weeks, was demonstrated in 5 of 31 patients with interrupted sutures versus 24 of 42 patients who had subcutis sutures. Episiotomy repair with subcutis polyglycolic acid (Dexon) offers significant advantages over traditional interrupted suture, both in terms of wound healing and resumption of sexual activity.