Richard L. Elliott

Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo

(2.4)-Dimethoxybenzylidene anabaseine dihydrochloride (GTS-21), a compound that interacts with rat neuronal nicotinic acetylcholine receptors (nAChRs), was evaluated using human recombinant nAChRs in vitro and various pharmacokinetic and behavioral models in rodents, dogs and monkeys. GTS-21 bound to human alpha 4 beta 2 nAChR (K1-20 nM) 100-fold more potently than to human alpha 7 nAChR, and was 18- and 2-fold less potent than (-)-nicotine at human alpha 4 beta 2 and alpha 7 nAChR, respectively. Functionally. GTS-21 stimulated [5H]dopamine release from rat striatal slices with an EC50 of 10 +/- 2 microM (250-fold less potent and 70% as efficacious as (-)-nicotine), an effect blocked by the nAChR antagonist dihydro-beta-erythroidine. However, GTS-21 did not stimulate human alpha 4 beta 2 nor human ganglionic nAChRs significantly. In vivo, GTS-21 had no adverse effect on dog blood pressure (< or = 2.5 micromol/kg i.v. bolus infusion), in marked contrast with (-)-nicotine, GTS-21 (-62 micromol/kg.s.e.) also did not cross-discriminate significantly with (-)-nicotine in rats and did not reduce temperature or locomotion in mice. Neither was it active in the elevated plus maze anxiety model (0.19-6.2 micromol/kg.IP) in normal mice. However, GTS-21 did improve learning performance of monkeys in the delayed matching-to-sample task (32-130 nmol/kg.i.m.).

Piperidine-derived γ-secretase modulators

This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.

The discovery of SB-435495: A potent, orally active inhibitor of lipoprotein-Associated phospholipase A2 for evaluation in man

The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.

Maximizing lipophilic efficiency: the use of Free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase.

This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

Novel 2-(2′-furo[3,2-b]pyridinyl) pyrrolidines: potent neuronal nicotinic acetylcholine receptor ligands

Abstract A novel series of 2-(2′-furo[3,2-b]pyridinyl) pyrrolidines has been synthesized and evaluated as novel nicotinic acetylcholine receptor ligands. Changing the pyrrolidine stereochemistry and N-substitution pattern afforded analogs with Ki values ranging from 2.7 to 97 nM. Rubidium efflux studies revealed that these compounds had intrinsic activities ranging from 9–58% that of nicotine in the IMR-32 cell line and 6–81% in the K177 cell line. The N(Me)-2(S) analog 3a demonstrated good selectivity in the K177 cell line (α4β2 receptor) versus the IMR-32 cells (α3βx receptor) and TE 671 cells (α1 neuromuscular receptor), and was a partial agonist with an EC50 value of 141 nM in dopamine release assay using rat striatal slices.

2-(Aryloxymethyl) azacyclic analogues as novel nicotinic acetylcholine receptor (nAChR) ligands

Abstract A series of 2-(aryloxymethyl) azetidine and pyrrolidine nAChR ligands in which the 3-pyridyl moiety of a previously described series 1 was replaced by a substituted phenyl group was explored. Aromatic substitution afforded analogues with K i values ranging from 3 to >10,000 nM. Generally, substitution at the ortho - and para -position was unfavorable, whereas electron-withdrawing groups at the meta -position improved the K i values.

Novel 3-deoxy-3-descladinosyl-6-O-methyl erythromycin a analogues. Synthesis and in vitro activity

Abstract A series of novel 3-deoxy-3-des-cladinosyl-6- O -methyl erythromycin A analogues has been synthesized and evaluated in vitro for antibacterial activity. These analogues were readily synthesized by tributyltin hydride-mediated radical reduction of a 3- O -xanthyl intermediate to afford the 3-deoxy macrolide. A number of oxime, carbonate, and carbamate derivatives were synthesized and evaluated for antibacterial activity. Overall, these analogues had fairly good antibacterial activity against gram-positive bacteria, although they were generally less potent than the corresponding 3- O -cladinosyl or 3-keto analogues. A series of novel 3-deoxy-3-des-cladinosyl-6- O -methyl erythromycin A analogues has been synthesized and evaluated in vitro for antibacterial activity. These analogues were readily synthesized by tributyltin hydride-mediated radical reduction of the 3- O -xanthyl intermediate to afford the 3-deoxy macrolide. A number of oxime, carbonate, and carbamate derivatives were synthesized and evaluated for antibacterial activity. Overall, these analogues had fairly good antibacterial activity against gram-positive bacteria, although they were generally less potent than the corresponding 3- O -cladinosyl or 3-keto analogues.

Phenyl pyrrolidine analogues as potent nicotinic acetylcholine receptor (nAChR) ligands

Abstract The synthesis and SAR of a series of 2-phenyl pyrrolidines as neuronal nAChR ligands are described. Substitution on the aryl ring had a dramatic effect on receptor binding affinity, with Ki values ranging from 46 nM to >10,000 nM. Analogues 8, 9, and 14 were the most potent ligands evaluated, having Ki values of 68 nM, 75 nM, and 46 nM; respectively.

Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.

Evaluation of basic, heterocyclic ring systems as templates for use as potassium competitive acid blockers (pCABs).

A variety of basic, heterocyclic templates has been reported as potassium-competitive, acid pump antagonists. Herein, we report a comparison of potencies of these templates and others to establish which offers the best start point for further systematic optimisation. Modifications were carried out to improve the developability profile of the more potent 1H-pyrrolo[2,3-c]pyridine template, affording molecules with improved overall in vitro characteristics versus the reported clinical candidate AR-H047108, and comparable to the clinically efficacious AZD-0865.