Pablo Morentin Gutierrez

(1R,2R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): a potent and highly selective cathepsin K inhibitor for the treatment of osteoarthritis.

Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.

Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.

Identification and design of a novel series of MGAT2 inhibitors

[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naїve, p<0.01) in plasma triacylglycerol (TAG) concentration.

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.

11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound C) inhibited liver 11β-HSD1 by >90% but led to only small improvements in metabolic parameters in high-fat diet (HFD)–fed male C57BL/6J mice. A 4-fold higher concentration produced similar enzyme inhibition but, in addition, reduced body weight (17%), food intake (28%), and glucose (22%). We hypothesized that at the higher doses compound C might be accessing the brain. However, when we developed male brain-specific 11β-HSD1 knockout mice and fed them the HFD, they had body weight and fat pad mass and glucose and insulin responses similar to those of HFD-fed Nestin-Cre controls. We then found that administration of compound C to male global 11β-HSD1 knockout mice elicited improvements in metabolic parameters, suggesting “off-target” mechanisms. Based on the patent literature, we synthesized another 11β-HSD1 inhibitor (MK-0916) from a different chemical series and showed that it too had similar off-target body weight and food intake effects at high doses. In summary, a significant component of the beneficial metabolic effects of these 11β-HSD1 inhibitors occurs via 11β-HSD1–independent pathways, and only limited efficacy is achievable from selective 11β-HSD1 inhibition. These data challenge the concept that inhibition of 11β-HSD1 is likely to produce a “step-change” treatment for diabetes and/or obesity.

Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687).

A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.

Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers

The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Kα is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with a novel PI3K inhibitor, AZD8835, currently in phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Kα and PI3Kδ with selectivity versus PI3Kβ, PI3Kγ, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor–positive (ER+) breast cancer cell lines BT474, MCF7, and T47D (sub-μmol/L GI50s). Consistent with this, AZD8835 demonstrated antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced antitumor activity (up to 92% regression). Combination partners were prioritized on the basis of our mechanistic insights demonstrating signaling pathway cross-talk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER+ breast cancer patients. In summary, AZD8835 IHDS delivers strong antitumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation. Mol Cancer Ther; 15(5); 877–89. ©2016 AACR.

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.

Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors

A series of neutral DGAT1 inhibitors with good potency and pharmacokinetics (PK) has been designed by modification of an acidic startpoint. This was achieved by selecting the acid with the highest ligand lipophilicity efficiency (LLE) and replacing the acid with neutral isosteres. PK properties (Fabs) were then improved by removing the sidechain to reduce molecular weight and polar surface area (PSA). Compound 13 has shown good cross-species PK, with pre-clinical efficacy and PK/PD relationships comparable to those previously described for acidic inhibitors.

Design and synthesis of a novel series of cyclohexyloxy-pyridyl derivatives as inhibitors of diacylglycerol acyl transferase 1

A novel series of potent diacylglycerol acyl transferase 1 inhibitors was developed from the clinical candidate AZD3988. Replacement of the phenyl cyclohexyl-ethanoate side chain with substituted oxy-linked side chains to introduce changes in shape and polarity, reduce lipophilicity and mask the hydrogen bond donors with internal hydrogen bond acceptors led to improvements in solubility, unbound clearance and excellent selectivity over the related enzyme acyl-coenzyme A:cholesterol acyltransferase 1. A comparison of the small molecule crystal structures of compound 4 and compound 28 is described. Compounds in this series have good ADMET properties and provide an exposure-dependent decrease in circulating plasma triglyceride levels in a rat oral lipid tolerance test.