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[Image: see text] We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound 21, a highly potent ATM inhibitor (ATM cell IC(50) 0.0028 μM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. In vivo, 21 in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone. Compound 21 was selected for preclinical evaluation alongside AZD0156.

A series of CCR2 antagonists containing halothiazoles were found to undergo an unexpected reaction with glutathione. Experiments revealed the structure–reactivity relationship and calculations suggest that competition between two reactions of a tautomer of the reactant (deprotonation and nucleophilic addition) governs the rate of this reaction.

Comparison of the human plasma protein binding data for a variety of drug discovery compounds indicates that compounds tend to be slightly more bound to human plasma proteins, than compared to plasma proteins from rats, dogs or mice. However, the majority of measurements from the pre-clinical species fall within 5-fold of the human plasma value, although there are some compounds that do show significantly different interspecies plasma protein binding.

Improving aqueous solubility is a challenge frequently faced within drug discovery programs. Herein we describe increases in solubility in two sub-series of GPR119 agonists through reduction of lipophilicity together with hydrogen bond acceptor modulation. Small molecule X-ray crystallography was utilised to investigate effects on solid state interactions.

Directed screening has identified a novel series of MMP13 inhibitors that possess good levels of activity whilst possessing excellent selectivity over related MMPs. The binding mode of the series has been solved by co-crystallisation and demonstrates an interesting mode of inhibition without interaction with the catalytic zinc atom.

The displacement of probes that bind selectively to subdomains IIA or IIIA on human serum albumin (HSA) by competing compounds has been followed using fluorescence spectroscopy, and has therefore been used to assign a primary binding site for these compounds in the presence and absence of fatty acids. The crystal structures have also been solved for three compounds: a matched pair of carboxylic acids whose binding strength to HSA unexpectedly decreased as the lipophilicity increased; and a highly bound sulphonamide that appeared not to displace the probes in the displacement assay. The crystallography results support the findings from the fluorescence displacement assay. The results indicate that drug binding to subdomain IB might also be important location for certain compounds.

A novel approach to inhibition of the alphavbeta3 integrin is described, which uses compounds designed to generate nM potency without using the arginine binding site.

A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.

A series of 2-(pyridinyl)pyrimidines were identified as potent GPR40 antagonists. Despite significant challenges related to improving the combination of potency and lipophilicity within the series, the compounds were optimised to identify a suitable in vivo probe compound, which was confirmed to exhibit pharmacology consistent with GPR40 antagonism.

The stability of drug-like molecules is one of the most important areas of the drug development process and Arrhenius studies can be used in order to predict the stability of compounds by performing forced degradation studies at elevated temperatures and then extrapolating the data to room temperature. Analysis of the activation energies calculated from 166 Arrhenius experiments performed on drug-like molecules in solution, using temperatures up to 90 °C, indicates that the mean activation energy for these degradations is 98.6 kJ/mol (23.6 kcal/mol). The impact on the predicted half-lives of employing different activation energies is discussed.

The hydroxylation of cycloalkanes at 25 °C by the syringe pump addition of tert-alkyl hydroperoxides (10 and 1 equiv based on catalyst) to deoxygenated acetonitrile containing cycloalkanes (0.64 M) and 0.61 mM of the catalyst, [FeIII2O(TPA)2(H2O)2]4+, is demonstrated to be a reaction which involves freely diffusing cycloalkyl radicals, i.e., free alkyl radicals.

Absolute rate constants for hydrogen atom abstraction by alkoxyl radicals from phenol, aniline, and diphenylamine have been measured in 14 solvents at room temperature by laser flash photolysis. For all three substrates the rate constants decline as the solvent becomes a stronger hydrogen-bond acceptor (HBA). Thus, on changing the solvent from CCl4 to CH3CN the rate constants decline by factors of 148, 7.1, and 4.7 for PhOH, PhNH2, and Ph2NH, respectively. The kinetic solvent effect for phenol correlates rather well with Abraham's scale of relative HBA activities of the solvents we have employed as measured as solutes in CCl4 solvent. This correlation is not quite so good with aniline and it is almost nonexistent for diphenylamine. With all three substrates the “deviant” solvents produce higher rate constants than would be expected from the value of the solvent and, generally, these are the solvents in which steric hindrance to hydrogen-bond formation would appear probable. The kinetic data for the three ...

The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.

A series of pyrimidine nitrile inhibitors of Cathepsin K with reduced glutathione reactivity has been identified and Molecular Core Matching (MoCoM) has been used to quantify the effect of an amino substituent at C5.

A quantitative assay involving the reaction of nitriles with glutathione and cysteine has been used as a simple in vitro screen to assess potential toxicity risk of candidate compounds in drug discovery. Studies have indicated that, when benchmarked with selected compounds, the reaction of the nitriles with glutathione can provide a useful tool for deciding whether or not to progress compounds in the absence of radiolabelling studies.

The oxidation of cyclooctane using tert-alkyl hydroperoxides under GoAggV conditions has been examined using selected alkyl hydroperoxides as mechanistic probes. The results indicate that the products are formed by alkoxyl radical-induced reactions, there being no need to invoke any chemistry involving high valent iron-oxo species.

The matched triplicate approach to lead optimisation offers a means of generating more robust quantitative structure activity relationship data and this rigour leads to better quality decision making and greater ability to predict optimal compounds within a series. One of the ultimate aims of this approach is to use the data generated to build more accurate predictive models to identify the best compounds within the exemplified chemical space in an efficient manner. This paper describes the continued application of this approach to the optimisation of a series of glucokinase activators. This second phase focussed primarily on the rational solution to plasma instability observed with the previous compounds and, hence, achieved acceptable oral exposure in the series. The campaign was completed by using the predictive power of Free-Wilson analysis based on the matched triplicate datasets to enable a focussed, matrix based endgame culminating in the identification of two development candidates, AZD3651 and AZD9485.

A pyrazolo-pyrimidinone based series of growth hormone secretagogue receptor type 1a (GHS-R1a) antagonists and inverse agonists were identified using a scaffold hop from known quinazolinone GHS-R1a modulators. Lipophilicity was reduced to decrease hERG activity while maintaining GHS-R1a affinity. SAR exploration of a piperidine substituent was used to identify small cyclic groups as a functional switch from partial agonists to neutral antagonists and inverse agonists. A tool compound was identified which had good overall properties and sufficient oral plasma and CNS exposure to demonstrate reduced food intake in mice through a mechanism involving GHS-R1a.

Monoacylglycerolacetyltransferase-2 (MGAT2) is a potential target for the treatment of type II diabetes. We report here the optimisation of a series of MGAT2 inhibitors with regard to their potency and permeability. Improvements in permeability, as measured by increased flux in a Caco-2 assay, were achieved through substitution at the 9-position of the core. We propose that reduction of the NH hydrogen-bond donor strength was primarily responsible for these effects.

Two series of amino-substituted 1,2,4- and 1,3,4-oxadiazole matched compounds were evaluated and found to have significant differences in their various physical and pharmaceutical properties. Experimental and computational techniques suggested that variation in hydrogen bond acceptor and donor strength were responsible for these effects.