Roger Edward Markwell

Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases

During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.

Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases.

We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.

Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases

As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.

Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases.

During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.

Aminophosphonic acid containing inhibitors of human collagenase: modification of the P1 residue

Abstract A series of peptidomimetic aminophosphonic acid derivatives was synthesized and evaluated in vitro for inhibition of human fibroblast collagenase activity. Incorporation of a bromonaphthalimidoethyl moiety at the P1 position led to potent inhibitors, such as 14a (IC50 0.02 μM).

2-[(substituted)phenyl]-5-[1-(2-phenylazacycloheptyl)methyl]-1H-pyrroles with high affinity and selectivity for the dopamine D3 receptor

Abstract A series of 2-[(substituted)phenyl]-5-[1-(2-phenylazacycloheptyl)methyl]-1 H -pyrroles ( 8 – 15 ) has been prepared to investigate the effect on affinity and selectivity for the dopamine D 3 receptor of modifying the substituent in the phenyl ring at the 2-position of the pyrrole. Sulfonate 7 and sulfonamides 12 , 14 , 15 were shown to have high affinities (pKis 8.0 – 8.7) and selectivities (100 – 150-fold) for the D 3 over the D 2 receptor.

Novel 2,5-disubstituted-1H-pyrroles with high affinity for the dopamine D3 receptor

Abstract A series of 2,5-disubstituted-1H-pyrroles (4–18) has been prepared based on replacement of the amide of sultopride 1 by a pyrrole ring. Subsequent modification of the basic side chain gave compounds with high affinity for the dopamine D3 receptor. In addition, 12 and 17 were shown to be D3 antagonists with 30-fold selectivity for the D3 receptor over the D2 receptor.

Inhibitors of human collagenase: dipeptide mimetics with lactam and azalactam moieties at the P2′P3′ position

Abstract A series of thiol-, aminophosphonic acid-, and hydroxamic acid-containing collagenase inhibitors, with lactam and azalactam P 2′ P 3′ substituents has been prepared and evaluated in vitro as inhibitors of human fibroblast collagenase. The most potent inhibitor was the hydroxamic acid 17a (IC50 12 nM). Introduction of a basic amino function into the lactam ring had little effect on potency, but greatly enhanced aqueous solubility.

β-, γ- and δ-Lactams as conformational constraints in ring-closing metathesis

The azabicycloalkenones 5, 6 and 7 were formed in excellent yields via ring-closing metathesis of the bis-alkenyl precursors 1, 2 and 3.

Synthesis of thiophenol derivatives as inhibitors of human collagenase

Abstract A series of peptidomimetic thiophenol derivatives has been prepared and evaluated in vitro as inhibitors of human fibroblast collagenase. Many of these compounds have IC50 values in the sub-micromolar range.