Peter T. Stephenson

Radical cyclisations of imines and hydrazones

Abstract Radical cyclisation of sp 3 carbon-centred radicals onto imines and hydrazones provides a new method for the synthesis of 5- and 6-membered ring nitrogen heterocycles. Cyclisation onto the electrophilic carbon of the C=N group and 5- exo stereoelectronic selectivity are the dominating mechanistic parameters. The C-centred radical intermediates were generated from benzeneselenyl precursors using Bu 3 SnH.

Imidazo[2′-3′-:6,5]dipyrido[3,2-b:2′,3′-e]-1,4-diazepines: non-nucleoside HIV-1 reverse transcriptase inhibitors with greater enzyme affinity than nevirapine

Abstract The chemistry and SAR of a new series of imidazo[2′,3′:6,5]dipyrido[3,2-b:2′,3′-e]-1,4-diazepines is described. These compounds show improved affinity for HIV-1 RTase and antiviral activity in vitro over nevirapine, which has undergone clinical trials.

An Imidazopiperidine Series of CCR5 Antagonists for the Treatment of HIV: The Discovery of N-{(1S)-1-(3-Fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propyl}acetamide (PF-232798)

Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.

Cyclisation of carbinyl radicals onto imines and hydrazones

The regioselectivity of intramolecular addition of sp3 carbon-centred radicals onto CN double bonds of imines and hydrazones is influenced by the position and polarisation of the CN bond.

CASCADE RADICAL CYCLISATIONS OF IMINES

Cascade radical reactions, initiated by cyclisation of sp3 carbon-centred radicals onto the C-atom of imines, have been used to develop a new protocol for the synthesis of a range of nitrogen heterocycles. The C-centred radical intermediates were generated from benzeneselenyl precursors using Bu3SnH. The aminyl radicals generated by cyclisation onto imines undergo further 5- or 6-exo cyclisation with suitably placed alkenes.

SYNTHESIS OF NITROGEN HETEROCYCLES USING TANDEM RADICAL CYCLISATION OF IMINES

Abstract Bicyclic nitrogen heterocycles have been synthesized by tandem cyclisation of sp 3 carbon-centred radicals onto the CN double bonds of imines to generate intermediate aminyl radicals, which undergo further cyclisation onto suitably positioned alkenes.

SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.

Inhaled adenosine A2A receptor agonists for the treatment of chronic obstructive pulmonary disease

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.

The design and discovery of novel amide CCR5 antagonists.

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SARs which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.

Design and optimisation of potent gp120-CD4 inhibitors.

The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.