Sam D. Groombridge

Use of small-molecule crystal structures to address solubility in a novel series of G protein coupled receptor 119 agonists: optimization of a lead and in vivo evaluation.

G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.

Rationally designing safer anilines: the challenging case of 4-aminobiphenyls.

We describe how we have been able to design 4-aminobiphenyls that are nonmutagenic (inactive in the Ames test). No such 4-aminobiphenyls were known to us, but insights provided by quantum mechanical calculations have permitted us to design and synthesize some examples. Importantly, the quantum mechanical calculations could be combined with predictions of other properties of the compounds that contained the 4-aminobiphenyls so that these remained druglike. Having found compounds that are not active, the calculations can provide insight into which factors (electronic and conformational in this case) are important. The calculations provided SAR-like information that was able guide the design of further examples of 4-aminobiphenyls that are not active in the Ames test.

Free-Wilson and Structural Approaches to Co-optimizing Human and Rodent Isoform Potency for 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors

11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. To demonstrate the value of 11β-HSD1 in preclinical models, we required inhibitors with good potency against both human and rodent isoforms. Herein, we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described-a data-driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD(7.4) range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycemic and body weight end points in murine disease models, where it demonstrated glucose and body weight efficacy at 300 mg/kg/day but only body weight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.

Property based optimisation of glucokinase activators – discovery of the phase IIb clinical candidate AZD1656

Glucokinase plays a central role in glucose homeostasis and small molecule activators of the glucokinase enzyme have been the subject of significant pharmaceutical research in the quest for agents capable of delivering improved glycaemic control. Here we describe our medicinal chemistry campaign to improve on our previously described development candidate in this area, AZD1092, focussed on removal of Ames liability and improved permeability characteristics. This work culminated in the superior compound AZD1656 which has progressed to phase 2 clinical trials.

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.

Discovery, optimisation and in vivo evaluation of novel GPR119 agonists.

GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.

Discovery of a series of 2-(pyridinyl)pyrimidines as potent antagonists of GPR40

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.

Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists

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.

Conformational restriction in a series of GPR119 agonists: Differences in pharmacology between mouse and human

A series of conformationally restricted GPR119 agonists were prepared based around a 3,8-diazabicyclo[3.2.1]octane scaffold. Examples were found to have markedly different pharmacology in mouse and human despite similar levels of binding to the receptor. This highlights the large effects on GPCR phamacology that can result from small structural changes in the ligand, together with inter-species differences between receptors.

Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome.