David Ellis

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.

Asymmetric synthesis of β-amino acid derivatives by Michael addition to chiral 2-aminomethylacrylates

Abstract The addition of lithium enolates to chiral aminomethylacrylates 7 and 8 proceeded with excellent diastereodifferentiation (up to 98% de) and provided an expeditious synthesis of homochiral β-aminomethylglutarates 9 and 10 , on a scale of up to 500g. The acrylates 7 and 8 , and their antipodes, should be useful synthons for the synthesis of β-amino acid derivatives.

Design and synthesis of pyridazinone-based 5-HT2C agonists

The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.

Synthesis of fluorescent enone derived α-amino acids

The development of a facile and general method for the preparation of enone derived alpha-amino acids is described. The key step involves a Horner-Wadsworth-Emmons reaction between an aspartic acid derived beta-keto phosphonate ester and a range of aldehydes resulting in the formation of highly functionalised alpha-amino acids in good yields. An efficient two-stage deprotection process using mild conditions was developed to give the parent alpha-amino acids. Application of this methodology has produced a novel fluorescent alpha-amino acid that has potential as a biological marker.

A one-pot, reductive amination/6-endo-trig cyclisation for the stereoselective synthesis of 6-substituted-4-oxopipecolic acids.

The first stereoselective synthesis of 2,6-trans-6-substituted-4-oxo-L-pipecolic acids using a tandem reductive amination/6-endo-trig cyclisation process is described. The sequential reduction and cyclisation mediated by sodium cyanoborohydride allowed the preparation of a series of highly functionalised 6-alkyl and 6-aryl analogues.

Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7

A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

Racemisation-free synthesis of chiral acylsulfonamides

Abstract The development and application of a synthesis of acylsulfonamide A avoiding racemisation of the labile benzylic stereogenic centre is described.

Application of epimerisation-free amide coupling conditions to the synthesis of matrix metalloprotease inhibitor intermediates

Abstract Coupling of the N-acyltert-leucine derivative 2 with a variety of amines 3a-g gave amides 4a-g in good to excellent yields (75–95%) with minimal epimerisation (≤ 3%) at thetert-leucine stereogenic centre. Limitations of the method are discussed.

Penicillin N-cyanosulphilmines; cyanamide/iodobenzene diacetate, a convenient cyanonitrene reagent for N-cyano sulphilmines, sulphoximines, phosphinimines and aziridines

Abstract Cyanamide with iodobenzene diacetate give cyanonitrene adducts of sulphides, sulphoxides, phosphines, and olefins. Penicillins give N -cyanosulphilimines, shown by intramolecular N-H...N hydrogen bonding or NMR ASIS to have β(S) stereochemistry.

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.