Rhys M. Jones

Inhalation by Design: Novel Ultra-Long-Acting β2-Adrenoreceptor Agonists for Inhaled Once-Daily Treatment of Asthma and Chronic Obstructive Pulmonary Disease That Utilize a Sulfonamide Agonist Headgroup

A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.

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.

Challenges of drug discovery in novel target space. The Discovery and Evaluation of PF-3893787: A Novel Histamine H4 Receptor Antagonist

We describe the development of novel benzimidazoles as small molecule histamine H4 receptor (H4R) antagonists and their profiling in rat early toxicity studies. The discovery and optimisation of a second series of pyrimidine based antagonists is then described culminating in the identification of the clinical development candidate 13 (PF-3893787). The pre-clinical profile of 13 (PF-3893787) is presented including the development of a translatable biomarker. Our pragmatic approach to target selection, safety assessment, and testing for efficacy faced numerous challenges and we share a number of lessons which the team learned and which will assist us and others in future drug discovery projects.

Interpretation and prediction of inhaled drug particle accumulation in the lung and its associated toxicity

The increasing use of poorly-soluble inhaled dry powder pharmaceuticals means that animal toxicology studies of these drugs frequently produce lung changes related to the physical presence of undissolved particulate material within the alveolar spaces. These changes are independent of any chemically- or pharmacologically-mediated toxicity and present a challenge to drug developers and regulators in that risk depends on the retained lung burden of undissolved drug material, rather than the delivered dose, systemic exposure or duration of dosing as traditionally used in risk assessment for inhaled compounds. The methodology presented uses basic pharmacokinetic principles to estimate lung particulate burdens achieved in rat inhalation toxicity studies for four inhaled compounds which have reached clinical evaluation. The estimated lung particulate burdens and associated histopathological findings were compared with published thresholds for similar effects caused by inert particulates such as titanium dioxide. Results of the analysis illustrate that regardless of the duration of the study, estimated lung burdens in excess of ∼1 mg drug per g lung were associated with adverse changes consistent with those described in the literature for inert insoluble particles. For all low solubility inhaled pharmaceuticals so far examined, the calculated steady-state retained lung burden of drug in humans is several orders of magnitude lower than that associated with adverse effects in human or animals.

Modulation of the partition coefficient between octanol and buffer at pH 7.4 and pKa to achieve the optimum balance of blood clearance and volume of distribution for a series of tetrahydropyran histamine type 3 receptor antagonists.

The relationship between rat pharmacokinetics and physicochemical parameters [the partition coefficient between octanol and buffer at pH 7.4 (log D(7.4)) and pKa] was studied for a series of tetrahydropyran compounds. Sixteen compounds ranging in log D(7.4) 0.1 to 1.8 were administered intravenously to rats, and the pharmacokinetic parameters were determined from blood concentration time curves. Across the series, a weak correlation was observed between log D(7.4) and blood clearance, suggesting that log D(7.4) values less than 0.5 were required to prevent clearance at hepatic blood flow. In terms of the volume of distribution (Vd), the compounds fell into three distinct subseries characterized by the number of basic centers and differences in ionization of each basic center at physiological pH. These were referred to as the monobasic, weak second base, and strong second base subseries. All the compounds exhibited Vd greater than body water, as would be expected from their lipophilic and basic nature. For a given clog P, the strong second base subseries showed higher Vd than the weak second base subseries, which in turn exhibited higher values than the monobasic subseries. In addition, for the weak second base subseries, Vd could be tuned by modulating the pKa of the second basic center. This relationship was rationalized in respect to the interactions of the ionizable centers with phospholipid heads in the cell membrane and/or lysosomal trapping. Compounds in the weak second base subseries showed optimal Vd, and when combined with a log D(7.4) of 0.1, driving to moderate blood clearance, one compound showed the optimal pharmacokinetic profile.

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.

A new methodology for predicting human pharmacokinetics for inhaled drugs from oratracheal pharmacokinetic data in rats

Prediction of pharmacokinetic (PK) profile for inhaled drugs in humans provides valuable information to aid toxicology safety assessment, evaluate the potential for systemic accumulation on multiple dosing and enable an estimate for the clinical plasma assay requirements. The accuracy in prediction of inhaled human PK profiles for seven inhaled drugs or drug candidates (salmeterol, salbutamol, formoterol, fluticasone propionate, budesonide, CP-325366 and UK-432097) was assessed using rat oratracheal solution and dry powder PK data. The prediction methodology incorporates allometric scaling and mean residence time (MRT) principles with a two compartmental PK approach. Across the range of compounds tested, the prediction of human inhaled maximum concentration (Cmax) and MRT was within 2-fold for 5 of the 7 compounds, providing an accuracy of prediction similar to the current methodologies used to predict human oral Cmax from preclinical data (). Administering as a dry powder formulation slowed the rat lung absorption rate of the least soluble compound (fluticasone propionate), impacting the prediction of Cmax and MRT. This flags the potential for preclinical studies with dry powder formulations to positively influence predictive accuracy, although further studies with low solubility inhaled drugs are required to confirm this. This study illustrates the value of preclinical assessment of PKs following administration to the lung, and provides a viable means of predicting the human PK profile for inhaled drugs.

Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.

Strategies to prevent N-acetyltransferase-mediated metabolism in a series of piperazine-containing pyrazalopyrimidine compounds

1. (1-Methyl-5-piperazin-1-yl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-(5-methyl-pyridin-2-yl)-amine (UK-469,413) was identified as a lead compound in a new medicinal chemistry programme. UK-469,413 had good physicochemical properties and was slowly metabolized by cytochromes P450 in rat and human liver microsomes. 2. In the rat in vivo the compound was rapidly cleared. Subsequent studies showed that UK-469,413 was rapidly acetylated in rat liver cytosol to an N-acetylpiperazine metabolite that was the major circulating metabolite in rat plasma in vivo. 3. Analogues of UK-469,413 containing the unsubstituted piperazine moiety were rapidly acetylated in rat liver cytosol and had high plasma clearance in the rat in vivo. These compounds were also acetylated in human liver cytosol and the N-acetyl metabolite was a major metabolite formed in incubations with cryopreserved human hepatocytes. 4. Using specific inhibitors, correlation analysis and expressed human N-acetyltransferase (NAT) enzymes the compounds were shown to be substrates of the polymorphically expressed NAT-2 isozyme. 5. Further experiments showed that it was possible to make small structural changes to the piperazine group that retained potency but prevented metabolism by NAT.

Discovery of Potent and Orally Bioavailable Macrocyclic Peptide–Peptoid Hybrid CXCR7 Modulators

The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side-chain diversity well beyond that of natural amino acids. At the same time, theoretical calculations and experimental assays were used to track and reduce the polarity while closely monitoring the physicochemical properties. This strategy led to the discovery of macrocyclic peptide-peptoid hybrids with high CXCR7 binding affinities (Ki < 100 nM) and measurable passive permeability (Papp > 5 × 10-6 cm/s). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.