Dann L. Parker

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.

Synthesis of α,β-disubstituted cycloalkenones through a sequence of olefin metathesis and oxidative rearrangement

Efficient syntheses of five-, six-, and seven-membered α,β-disubstituted cycloalkenones were achieved. Ring-closing metathesis and allylic oxidative rearrangement were the key steps in this route. To make substituted cycloalkenes from triene substrates constituted of two monosubstituted double bonds and one α,α-disubstituted double bond, ethylene was found to successfully promote equilibria among ring closing-ring opening-ring closing processes.

Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes.

A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3-phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142.

Development of a novel tricyclic class of potent and selective FIXa inhibitors.

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

Use of fluoroalkyl as a latent group for internal alkylation: application to the synthesis of bridged tetrahydrofluorenones.

Tetrahydrofluorenones which possess a C9a-fluoroalkyl substituent were efficiently converted to tetrahydrofluorenones which contain a ring bridging C9a-C2. Conditions include a stepwise sequence of conversion to an alkyl bromide followed by treatment with base, and a direct cyclization by treatment with lithium chloride in DMF heated to 150 degrees C.