Molecular hybridization yields triazole bronchodilators for the treatment of COPD.

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

The integration of solid-form informatics into solid-form selection.

OBJECTIVES: To demonstrate how the use of structural informatics during drug development assists with the assessment of the risk of polymorphism and the selection of a commercial solid form. METHODS: The application of structural chemistry knowledge derived from the hundreds of thousands of crystal structures contained in the Cambridge Structural Database to drug candidates is described. Examples given show the comparison of intermolecular geometries to database-derived statistics, the use of Full Interaction Maps to assess polymorph stability and the calculation of hydrogen bond propensities to provide assurance of a stable solid form. The software tools used are included in the Cambridge Structural Database System and the Solid Form Module of Mercury. KEY FINDINGS: The early identification of an unusual supramolecular motif in the development phase of maraviroc led to further experimental work to find the most stable polymorph. Analyses of two polymorphs of a pain candidate drug demonstrated how consideration of molecular conformation and intermolecular interactions were used for the assessment of relative stability. Informatics analysis confirmed that the solid form of crizotinib, a monomorphic system, had a low risk of polymorphism. CONCLUSIONS: The application of informatics-based assessment of new chemical entities complements experimental studies and provides a deeper understanding of the qualities of the structure. The information provided by structural analyses is incorporated into the assessment of risk. Informatics techniques are quick to apply and are straightforward to use, allowing an assessment of progressing drug candidates.

Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability.

The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.

Inhalation by design: novel tertiary amine muscarinic M3 receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.

A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.

Discovery and synthesis of a new class of opioid ligand having a 3-azabicyclo[3.1.0]hexane core. An example of a 'magic methyl' giving a 35-fold improvement in binding.

In looking for a novel achiral µ opioid receptor antagonist for the treatment of pruritus, we designed and synthesised azabicyclo[3.1.0]hexane compounds as a new class of opioid ligand. During optimisation, an addition of a single methyl resulted in a 35-fold improvement in binding. An early example from the series had excellent µ opioid receptor antagonist antagonist activity and was very effective in an in vivo pruritus study.

Inhalation by design: dual pharmacology ß-2 agonists/M3 antagonists for the treatment of COPD.

This paper describes the successful design and development of dual pharmacology ß-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.

Inhalation by design: novel ultra-long-acting ß(2)-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 ß(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.

Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans.

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

Hydrogen-bond motifs in the crystals of hydrophobic amino acids.

A computer program has been developed to survey a set of crystal structures for hydrogen-bond motifs. Possible ring and chain motifs are generated automatically from a user-defined list of interacting molecular fragments and intermolecular interactions. The new program was used to analyse the hydrogen-bond networks in the crystals of 52 zwitterionic alpha-amino acids. All the possible chain motifs (repeating 1-4 molecules) are frequent, while the frequency of ring motifs (2-6 molecules) ranges from 0 to 85% of the structures. The list of motifs displayed by each structure reveals structural similarities and it can be used to compare polymorphs. The motifs formed in cocrystals of alpha-amino acids and in crystals of beta- and gamma-amino acids are similar to those of alpha-amino acids.

The Claisen rearrangement approach to fused bicyclic medium-ring oxacycles.

The synthesis of five fused-bicyclic medium-ring lactones carrying identical ring-fusion to that in the polyether toxins is described using an enolate hydroxylation, intramolecular hydrosilation, Claisen rearrangement sequence.

A quick method for the quantitative analysis of mixtures. 1. Powder X-ray diffraction.

A method of analyzing mixtures of APIs and excipients using X-ray powder diffraction is described. It uses a simple algorithm based on linear regression in which the pure component phases are fitted to the mixture pattern using linear least squares. Unlike many methods that use only the peaks in the powder pattern, this technique uses all the measured data points in the 2theta scan with minimal data processing. In practice, using 33 different samples on three diffractometers, the method can be shown to work well for mixtures with up to three components, giving mean errors between 1.7% and 3.9% for two-phase mixtures, and 4.0% and 8.6% for three-phase mixtures. These results compare favorably to those given by traditional Rietveld refinement. It is also shown that the Bruker GADDS system, which is designed for high throughput crystallization experiments, is capable of giving results of comparable accuracy to those derived from traditional, single sample diffractometers. It is possible to identify those mixtures for which one or more pure phase X-ray powder patterns are not available with a detection limit around 10%. The techniques are implemented in the PolySNAP computer program. The method requires very little computer time or user interaction.

Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis.

Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.

Knowledge-based model of hydrogen-bonding propensity in organic crystals.

A new method is presented to predict which donors and acceptors form hydrogen bonds in a crystal structure, based on the statistical analysis of hydrogen bonds in the Cambridge Structural Database (CSD). The method is named the logit hydrogen-bonding propensity (LHP) model. The approach has a potential application in identifying both likely and unusual hydrogen bonding, which can help to rationalize stable and metastable crystalline forms, of relevance to drug development in the pharmaceutical industry. Whilst polymorph prediction techniques are widely used, the LHP model is knowledge-based and is not restricted by the computational issues of polymorph prediction, and as such may form a valuable precursor to polymorph screening. Model construction applies logistic regression, using training data obtained with a new survey method based on the CSD system. The survey categorizes the hydrogen bonds and extracts model parameter values using descriptive structural and chemical properties from three-dimensional organic crystal structures. LHP predictions from a fitted model are made using two-dimensional observables alone. In the initial cases analysed, the model is highly accurate, achieving approximately 90% correct classification of both observed hydrogen bonds and non-interacting donor-acceptor pairs. Extensive statistical validation shows the LHP model to be robust across a range of small-molecule organic crystal structures.

Luminescent digold ethynyl thienothiophene and dithienothiophene complexes; their synthesis and structural characterisation.

A series of protected and terminal dialkynes with extended pi-conjugation through the fused oligothienyl linker unit in the backbone, 2,5-bis(trimethylsilylethynyl)thieno[3,2-b]thiophene 1a, 5,5'-bis(trimethylsilylethynyl)dithieno[3,2-b:2',3'-d]thiophene 1b, 2,5-bis(ethynyl)thieno[3,2-b]thiophene 2a, 5,5'-bis(ethynyl)dithieno[3,2-b:2',3'-d]thiophene 2b, has been synthesized and characterised. The digold alkynyl complexes [(Ph3P)Au(C[triple bond]C)(C6H2S2)(C[triple bond]C)Au(PPh3)] 3a and [(Ph3P)Au(C[triple bond]C)(C8H2S3)(C[triple bond]C)Au(PPh3)] 3b have then been prepared by the reaction of two equivalents of Ph3PAuCl and a methanolic KOH solution of 1a and 1b, respectively. The complexes have been characterised spectroscopically. The crystal structures show that the gold centres adopt a linear two-coordinate geometry appropriate for Au(i) complexes. Within the crystals adjacent molecules are linked by Au...S intermolecular interactions in the range 3.48-3.89 A, but there are no short Au...Au contacts. The absence of Au...Au interactions in solution is confirmed by UV/visible absorption and emission spectroscopy, the spectra being dominated by ligand-centred pi-pi* interactions.

Solid state dehydration processes: mechanism of water loss from crystalline inosine dihydrate.

The solid state dehydration of inosine dihydrate has been investigated using powder X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, dynamic vapor sorption, hot stage microscopy, 13C solid state NMR, and variable temperature Fourier transform infrared spectroscopy. The information obtained from these experiments has been combined with an analysis of the crystallographic packing of inosine dihydrate and its two anhydrous polymorphs to yield mechanistic insights into the modes of water loss. The results allow an understanding of why, surprisingly, the dehydration of the dihydrate is always found to give the anhydrous, metastable, alpha-form.

Synthesis, characterisation and optical spectroscopy of platinum(II) di-ynes and poly-ynes incorporating condensed aromatic spacers in the backbone.

A series of protected and terminal dialkynes with extended pi-conjugation through a condensed aromatic linker unit in the backbone, 1,4-bis(trimethylsilylethynyl)naphthalene, 1,4-bis(ethynyl)naphthalene, 9,10-bis(trimethylsilylethynyl)anthracene, 9,10-bis(ethynyl)anthracene, have been synthesized and characterized spectroscopically. The solid-state structures of and have been confirmed by single crystal X-ray diffraction studies. Reaction of two equivalents of the complex trans-[Ph(Et(3)P)(2)PtCl] with an equivalent of the terminal dialkynes 1,4-bis(ethynyl)benzene and, in (i)Pr(2)NH-CH(2)Cl(2), in the presence of CuI, at room temperature, afforded the platinum(II) di-ynes trans-[Ph(Et(3)P)(2)Pt-C[triple bond, length as m-dash]C-R-C[triple bond, length as m-dash]C-Pt(PEt(3))(2)Ph](R = benzene-1,4-diyl; naphthalene-1,4-diyl and anthracene-9,10-diyl ) while reactions between equimolar quantities of trans-[((n)Bu(3)P)(2)PtCl(2)] and under similar conditions readily afforded the platinum(II) poly-ynes trans-[-((n)Bu(3)P)(2)Pt-C[triple bond]C-R-C[triple bond]C-](n)(R = naphthalene-1,4-diyl and anthracene-9,10-diyl ). The Pt(II) diynes and poly-ynes have been characterized by analytical and spectroscopic methods, and the single crystal X-ray structures of and have been determined. These structures confirm the trans-square planar geometry at the platinum centres and the linear nature of the molecules. The di-ynes and poly-ynes are soluble in organic solvents and readily cast into thin films. Optical spectroscopic measurements reveal that the electron-rich naphthalene and anthracene spacers create strong donor-acceptor interactions between the Pt(II) centres and conjugated ligands along the rigid backbone of the organometallic polymers. Thermogravimetry shows that the di-ynes possess a somewhat higher thermal stability than the corresponding poly-ynes. Both the Pt(II) di-ynes and the poly-ynes exhibit increasing thermal stability along the series of spacers from phenylene through naphthalene to anthracene.

A concise synthesis of the octalactins.

The total synthesis of octalactins A and B has been achieved in 15 steps (longest linear sequence) and 10% overall yield from commercially available materials. Key steps include the Paterson-Aldol reaction for the rapid assembly of the carbonate 46, methylenation of 46 and subsequent Claisen rearrangement of the corresponding alkenyl-substituted cyclic ketene acetal to provide the core unsaturated medium-ring lactone 47, and the use of enzyme-mediated acetate deprotection in the presence of a medium-ring lactone.

Construction of multiporphyrin arrays using ruthenium and rhodium coordination to phosphines.

The synthesis of linear multiporphyrin arrays with mono- and bisphosphine-substituted porphyrins as ligand donors and ruthenium(II) or rhodium(III) porphyrins as ligand acceptors is described. With appropriate amounts of the building blocks mixed, linear dimeric and trimeric arrays have been synthesized and analyzed by (1)H NMR and (31)P NMR spectroscopy. The Ru/Rh acceptor porphyrins can be located either at the periphery or in the center of the array. Likewise, the monophosphine porphyrins can be positioned at the periphery, thus allowing a high degree of freedom in the overall composition of the arrays. This way, both donor and acceptor porphyrins can act as chain extenders or terminators. One of the trimeric complexes with two nickel and one ruthenium porphyrin has also been analyzed by X-ray crystallography. Attempts have also been made to synthesize higher order arrays by mixing appropriate amounts of the porphyrins; however, from the NMR data it cannot be concluded if monodisperse five, seven, or nine porphyrin arrays are present or if the solutions are composed of a statistical mixture of smaller and larger arrays.

Phosphine and phosphonite complexes of a ruthenium(II) porphyrin. 1. Synthesis, structure, and solution state studies.

We have investigated the effect of complexation of different phosphorus ligands on the stability, solid state structure, and spectroscopic properties (NMR, IR, UV-vis) of a 5,15-diphenyl-substituted ruthenium porphyrin, (MeOH)Ru(II)(CO)(DPP) 2 [DPP = 5,15-bis(3',5'-di-tert-butyl)phenyl-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin]. The ligands used are PPh(3), diphenyl(phenylacetenyl)phosphine (DPAP), bis(diphenylphosphino)acetylene (DPPA), tris(phenylacetenyl)phosphine [(PA)(3)P], and diethyl (phenylacetenyl)phosphonite [PAP(OEt)(2)]. The mono-phosphine complexes (PR(3))Ru(II)(CO)(DPP) are readily formed in solution in quantitative yields. The complexes display association constants ranging from 1.2 x 10(4) M(-1) for PPh(3) to 4.8 x 10(6) M(-1) for PAP(OEt)(2). The weak association of PPh(3) does not correlate with its pK(a), delta((31)P), or cone angle value and is attributed to steric effects. Due to their kinetic lability, which is shown by 2D NMR spectroscopy, and the weakening of the carbonyl ligand via a trans effect, the mono-phosphine complexes could not be isolated. IR spectroscopy gives the relative order of pi-acceptor strength as PPh(3) < DPAP, DPPA < (PA)(3)P < PAP(OEt)(2), whereas the relative order of the sigma-donor strength is PPh(3) < (PA)(3)P < DPAP, DPPA < PAP(OEt)(2), based on the calculated pK(a) values and on the (31)P((1)H) NMR chemical shifts of the ligands. The chemical shift differences in the (31)P9(1)H)) NMR spectra upon ligand binding display a linear correlation with the calculated pK(a) values of the protonated ligands HPR(3)(+); we propose that the pK(a), and probably other electronic properties, of a specific phosphorus ligand can be estimated on the basis of the chemical shift difference Deltadelta((31)P) upon complexation to a metalloporphyrin. The bis-phosphine complexes can be isolated in pure form by crystallization from CHCl(3)-MeOH solutions using excess ligand. Association of the second ligand is in the same order of magnitude as the first binding for the phosphines, but the second phosphonite binding is decreased by a factor of about 100. The solid state structures show only marginal differences in the geometrical parameters. The calculated and the crystallographic cone angles of the ligands generally do not match, apart from the values obtained for PAP(OEt)(2).