Robert R. Wilkening

An efficient synthesis of 2-substituted-thio-6-hydroxyethyl-penem-3-carboxylic acids via 2-thioxopenams

Abstract Allyl and p -nitrobenzyl (5R, 6S)-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-thioxopenam-3-carboxylates ( 19 ) were synthesized by base mediated cyclization of the corresponding 1-carboxylmethyl-4-phenoxy (thiocarbonyl)thio-2-azetidinones ( 16 ). The thioxopenams underwent alkylation and Michael reactions to produce 2-alkylthio- and 2-alkenylthio-penem derivatives 20 and 21 .

Synthesis and activity of 2-(sulfonamido)methyl-carbapenems: Discovery of a novel, anti-MRSA 1,8-naphthosultam pharmacophore

A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.

The synthesis of novel 8a-aza-8a-homoerythromycin derivatives via the beckmann rearrangement of (9z)-erythromycin a oxime

The (9E)-oxime of erythromycin A (1) was isomerized to the (9Z)-isomer 2 in the presence of strong base. Stereospecific Beckmann rearrangement of the (9Z)-oxime led to a series of novel 8a-aza-8a- homoerythromycin A derivatives. In vitro data is provided that shows the 8a-methyl derivative 10 to be equally active with its positional isomer azithromycin.

Synthesis and properties of 2-(naphthosultamyl)methyl-carbapenems with potent anti-MRSA activity: discovery of L-786,392.

A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.

Benzothiazolylthio carbapenems: potent anti-MRSA agents

Abstract A series of sulfur-linked benzothiazolyl carbapenems has been prepared and evaluated against a battery of microorganisms. Many of the compounds displayed good activity against methicillin-resistant Staphylococcus aureus (MRSA). Data is presented which delimits the pharmacophore and provides a preliminary SAR.

Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase.

Orally bioavailable inhibitors of β-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein.

Control of rat tail skin temperature regulation by estrogen receptor-beta selective ligand.

OBJECTIVE To test the role of ERbeta in the control of estrogen-dependent thermoregulation in rats. METHODS Test the ability of an ERbeta-selective ligand to suppress the elevation in basal rat tail skin temperature (TST) caused by ovariectomy (OVX). RESULTS ERbeta-19 is a tetrahydrofluorenone ERbeta-selective ligand that displaces 0.1 nM estradiol from ERbeta with an IC50 of 1.8 nM compared to an IC50 of 141 nM for ERalpha. Like estradiol, it acts as an agonist on ERbeta-mediated transactivation and transrepression with 25- and 60-fold selectivity, respectively, over ERalpha-controlled transcription. Administration of estradiol to estrogen-depleted rats suppresses the ovariectomy-induced elevation of TST. Similar treatment of OVX rats with ERbeta-19 also results in suppression of elevated TST. However, in contrast to estradiol, ERbeta-19 does not suppress body weight, does not increase uterine weight, nor does it stimulate uterocalin biomarker expression which is under the control of ERalpha. Thus, the ERbeta-19 suppression of rat TST is mediated by ERbeta without eliciting the activity of ERalpha. CONCLUSION Estrogen-sensitive thermoregulation in ovariectomized rats can be controlled by an ERbeta-selective ligand.

Preparation and activities of 4″-epi and 4″-deoxy-4″-amino analogs derived from 9-deoxo-8a-aza-8a-homoerythromycin A☆

Abstract The preparation and biological activity of the novel aza macrolides 6, 8, 11–13 and 15–20 are reported. These analogs display in vitro antibacterial properties that are superior to erythromycin A.

Novel transannular rearrangements of azalide iminoethers

Abstract The transannular reactions between the aglycone hydroxyl groups and the iminoether and lactone groups of the 9a- and 8a-azalide iminoethers 4 and 5 were investigated under a variety of conditions. Translactonization by the 11-hydroxyl groups of 4 and 5 were found to give the corresponding 13-membered iminoethers 21 and 9. The thermal rearrangement of 4 produced an epimeric mixture of the 9,11-iminoethers 15 and 16. Further elaboration of isomer 16 produced 8-epi azithromycin 20. Finally, we have proposed an alternative structure, the amino γ-lactone 25, for one of the reported products (14) from the Beckmann rearrangement of erythromycin A (9E)-oxime 13. An authentic sample of 9a-aza-9a-homoerythromycin A 14 was prepared in three steps from iminoether 4.

Structure–activity-relationship of amide and sulfonamide analogs of omarigliptin

A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.