William V. Murray

Microwave enabled external carboxymethyl substituents in the ring-closing metathesis

The ring-closing metathesis of diolefin substrates containing an external carboxymethyl substituent is presented. The reaction is enabled through microwave irradiation allowing greatly enhanced yields and conversion rates. The reaction results in the formation of carboxymethyl substituted dihydropyrroles, dihydrofurans, and cyclopentenes. In certain cases, pyrroles are formed through further in situ oxidation.

Synthesis and evaluation of 2,7-diamino-thiazolo[4,5-d] pyrimidine analogues as anti-tumor epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.

Direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes via Pd/Cu-catalyzed phosphonium coupling

The first chemoselective direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes has been achieved via C-H/C-OH bond activations with direct C(sp(2))-C(sp) bond formation, which is in line with ideal synthesis using readily available materials.

Synthesis and discovery of 2,3-dihydro-3,8-diphenylbenzo[1,4]oxazines as a novel class of potent cholesteryl ester transfer protein inhibitors.

2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazines were identified as a new class of potent cholesteryl ester transfer protein inhibitors. The most potent compound 6a (IC50=26 nM) possessed a favorable pharmacokinetic profile with good oral bioavailability in rat (F=53%) and long human liver microsome stability (t(1/2)=62 min). It increased HDL-C in human CETP transgenic mice and high-fat fed hamsters. The structure and activity relationship of this series will be described in this Letter.

Synthetic staurosporines via a ring closing metathesis strategy as potent JAK3 inhibitors and modulators of allergic responses.

The synthesis and biological evaluation of JAK3 based staurosporine compounds is described. The compounds are constructed completely de novo, and a ring closing metathesis strategy is used to assemble the sugar mimetic portion. These analogs show potent JAK3 activity against isolated enzyme and in T-cells. One analog (32) showed unique biological effects during in vitro and in vivo tests including inhibition of STAT5 phosphorylation, blockade of mast cell responses, and reduction of JAK3 based effects in mice models of allergic disease.

Synthesis of densely functionalized pyrrolidinone templates by an intramolecular oxo-Diels-Alder reaction

Abstract Preparation of densely functionalized pyrrolidinone templates, is a challenge for synthetic chemists. These templates are important building blocks for novel conformationally constrained natural products or for library generation of highly functionalized bi or polycyclic compounds. We discovered that trienes 6a – j undergo facile stereoselective intramolecular Diels–Alder reactions to generate densely functionalized cis fused pyrrolidinone templates 1a – j . These reactions allow for directed remote hydroxylation with complete control of stereochemistry.

Synthesis and structure–activity relationship of 7-azaindole piperidine derivatives as CCR2 antagonists

The synthesis and structure-activity relationship of a series of 7-azaindole piperidine derivatives are described. SAR studies led to the discovery of the potent CCR2 antagonists displaying IC(50) values in the nanomolar range. The representative compound 15 showed reasonable P450 and pharmacokinetics profile.

Arylpiperazine substituted heterocycles as Selective α1a adrenergic antagonists

Abstract Antagonists of the α1-adrenergic receptors (α1-ARs) are useful for the treatment of benign prostatic hyperplasia. A series of potent and subtype-selective α1a-AR antagonists has been synthesized, displaying in vitro binding affinity in the low the nanomolar range.

6-Oxa isosteres of anacardic acids as potent inhibitors of bacterial histidine protein kinase (HPK)-mediated two-component regulatory systems

A series of 6-oxa isosteres of anacardic acids (6-higher alkyl/alkenyl-2-hydroxybenzoic acids) was synthesised and several members were discovered to be among the most potent inhibitors (IC50 values < or = 5 microM) of the bacterial two-component regulatory systems, KinA/SpoOF and NRII/NRI, reported to date. The Gram-positive antibacterial activity in selected strains is also presented.

Novel arylpiperazines as selective α1-adrenergic receptor antagonists

A novel series of arylpiperazines has been synthesized and identified as antagonists of α1a adrenergic receptor (α1a-AR) implicated in benign prostatic hyperplasia. These compounds selectively bind to membrane bound α1a-AR with Kis as low as 0.66 nM. As such, these potentially represent a viable treatment for BPH without the side effects associated with known α1-adrenergic antagonists.