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Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O -dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.

Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD. The first study ( NCT03248882 ) examined the effects of monotherapy with a novel ACC1/2 inhibitor, PF-05221304 (2, 10, 25 and 50 mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study ( NCT03776175 ) investigated the effects of PF-05221304 (15 mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300 mg BID), versus placebo after 6 weeks of treatment. The primary endpoint in both studies was percent change from baseline in liver fat assessed by magnetic resonance imaging-proton density fat fraction. Dose-dependent reductions in liver fat reached 50-65% with PF-05221304 monotherapy doses ≥10 mg QD; least squares mean (LSM) 80% confidence interval (CI) was -7.2 (-13.9, 0.0), -17.1 (-22.7, -11.1), -49.9 (-53.3, -46.2), -55.9 (-59.0, -52.4) and -64.8 (-67.5, -62.0) with 16 weeks placebo and PF-05221304 2, 10, 25 and 50 mg QD, respectively. The overall incidence of adverse events (AEs) did not increase with increasing PF-05221304 dose, except for a dose-dependent elevation in serum triglycerides (a known consequence of hepatic acetyl-coenzyme A carboxylase (ACC) inhibition) in 23/305 (8%) patients, leading to withdrawal in 13/305 (4%), and a dose-dependent elevation in other serum lipids. Co-administration of PF-05221304 and PF-06865571 lowered liver fat compared to placebo (placebo-adjusted LSM (90% CI) -44.6% (-54.8, -32.2)). Placebo-adjusted LSM (90% CI) reduction in liver fat was -44.5% (-55.0, -31.7) and -35.4% (-47.4, -20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Recent studies suggest that excess dietary fructose contributes to metabolic dysfunction by promoting insulin resistance, de novo lipogenesis (DNL), and hepatic steatosis, thereby increasing the risk of obesity, type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), and related comorbidities. Whether this metabolic dysfunction is driven by the excess dietary calories contained in fructose or whether fructose catabolism itself is uniquely pathogenic remains controversial. We sought to test whether a small molecule inhibitor of the primary fructose metabolizing enzyme ketohexokinase (KHK) can ameliorate the metabolic effects of fructose., Methods: The KHK inhibitor PF-06835919 was used to block fructose metabolism in primary hepatocytes and Sprague Dawley rats fed either a high-fructose diet (30% fructose kcal/g) or a diet reflecting the average macronutrient dietary content of an American diet (AD) (7.5% fructose kcal/g). The effects of fructose consumption and KHK inhibition on hepatic steatosis, insulin resistance, and hyperlipidemia were evaluated, along with the activation of DNL and the enzymes that regulate lipid synthesis. A metabolomic analysis was performed to confirm KHK inhibition and understand metabolite changes in response to fructose metabolism in vitro and in vivo. Additionally, the effects of administering a single ascending dose of PF-06835919 on fructose metabolism markers in healthy human study participants were assessed in a randomized placebo-controlled phase 1 study., Results: Inhibition of KHK in rats prevented hyperinsulinemia and hypertriglyceridemia from fructose feeding. Supraphysiologic levels of dietary fructose were not necessary to cause metabolic dysfunction as rats fed the American diet developed hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis, which were all reversed by KHK inhibition. Reversal of the metabolic effects of fructose coincided with reductions in DNL and inactivation of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP). We report that administering single oral doses of PF-06835919 was safe and well tolerated in healthy study participants and dose-dependently increased plasma fructose indicative of KHK inhibition., Conclusions: Fructose consumption in rats promoted features of metabolic dysfunction seen in metabolic diseases such as T2D and NASH, including insulin resistance, hypertriglyceridemia, and hepatic steatosis, which were reversed by KHK inhibition., (Copyright © 2021 Pfizer Inc. Published by Elsevier GmbH.. All rights reserved.)

Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 ( 8 ), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.

Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 ( 12 ), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.

Acetyl-CoA carboxylase (ACC) catalyses the first step of de novo lipogenesis (DNL). Pharmacologic inhibition of ACC has been of interest for therapeutic intervention in a wide range of diseases. We demonstrate here that ACC and DNL are essential for platelet production in humans and monkeys, but in not rodents or dogs. During clinical evaluation of a systemically distributed ACC inhibitor, unexpected dose-dependent reductions in platelet count were observed. While platelet count reductions were not observed in rat and dog toxicology studies, subsequent studies in cynomolgus monkeys recapitulated these platelet count reductions with a similar concentration response to that in humans. These studies, along with ex vivo human megakaryocyte maturation studies, demonstrate that platelet lowering is a consequence of DNL inhibition likely to result in impaired megakaryocyte demarcation membrane formation. These observations demonstrate that while DNL is a minor quantitative contributor to global lipid balance in humans, DNL is essential to specific lipid pools of physiological importance.

Acylcarnitines have been identified in human and animal metabolomic-profiling studies as urinary markers of radiation exposure, a result which is consistent with their cytoprotective effects and roles in energy metabolism. In the present work, a rapid method for quantitation of the more abundant acylcarnitines in human urine is developed using a valuable set of samples from cancer patients who received total body irradiation (TBI) at Memorial Sloan Kettering Cancer Center. The method uses solid-phase extraction (SPE) processing followed by differential mobility spectrometry (DMS with ethyl acetate modifier) tandem mass spectrometry (ESI-DMS-MS/MS) with deuterated internal standards. The analyzed human urine samples were collected from 38 individual patients at three time points over 24 h during and after the course of radiation treatment, a design allowing each patient to act as their own control and creatinine normalization. Creatinine-normalized concentrations for nine urinary acylcarnitine (acyl-CN) species are reported. Six acyl-CN species were reduced at the 6 h point. Acetylcarnitine (C2:0-CN) and valerylcarnitine (C5:0-CN) showed recovery at 24 h, but none of the other acyl-CN species showed recovery at that point. Levels of three acyl-CN species were not significantly altered by radiation. This rapid quantitative method for clinical samples covers the short- and medium-chain acylcarnitines and has the flexibility to be expanded to cover additional radiation-linked metabolites. The human data presented here indicates the utility of the current approach as a rapid, quantitative technique with potential applications by the medical community, by space research laboratories concerned with radiation exposure, and by disaster response groups.

Background & Aims: Disordered metabolism, steatosis, hepatic inflammation, and fibrosis contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) catalyzes the first committed step in de novo lipogenesis (DNL) and modulates mitochondrial fatty acid oxidation. Increased hepatic DNL flux and reduced fatty acid oxidation are hypothesized to contribute to steatosis. Some proinflammatory cells also show increased dependency on DNL, suggesting that ACC may regulate aspects of the inflammatory response in NASH. PF-05221304 is an orally bioavailable, liver-directed ACC1/2 inhibitor. The present studies sought to evaluate the effects of PF-05221304 on NASH pathogenic factors in experimental model systems., Methods: The effects of PF-05221304 on lipid metabolism, steatosis, inflammation, and fibrogenesis were investigated in both primary human-derived in vitro systems and in vivo rodent models., Results: PF-05221304 inhibited DNL, stimulated fatty acid oxidation, and reduced triglyceride accumulation in primary human hepatocytes, and reduced DNL and steatosis in Western diet-fed rats in vivo, showing the potential to reduce hepatic lipid accumulation and potentially lipotoxicity. PF-05221304 blocked polarization of human T cells to proinflammatory but not anti-inflammatory T cells, and suppressed activation of primary human stellate cells to myofibroblasts in vitro, showing direct effects on inflammation and fibrogenesis. Consistent with these observations, PF-05221304 also reduced markers of inflammation and fibrosis in the diethylnitrosamine chemical-induced liver injury model and the choline-deficient, high-fat-fed rat model., Conclusions: The liver-directed dual ACC1/ACC2 inhibitor directly improved multiple nonalcoholic fatty liver disease/NASH pathogenic factors including steatosis, inflammation, and fibrosis in both human-derived in vitro systems and rat models., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

PF-04991532 ((S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl) propanamido) nicotinic acid) is a glucokinase activator designed to achieve hepato-selectivity via organic anion-transporting polypeptides (OATP)s, so as to minimize systemic hypoglycemic effects. This study investigated the effect of OATP1B1/1B3 inhibition and renal impairment on PF-04991532 oral pharmacokinetics. Cyclosporine (600 mg single dose) increased mean area under the plasma curve (AUC) of PF-04991532 by approximately threefold in healthy subjects. In a renal impairment study, PF-04991532 AUC values were ~ 2.3-fold greater in subjects with mild, moderate, and severe kidney dysfunction, compared with healthy subjects. Physiologically-based pharmacokinetic (PBPK) model parameterizing hepatic and renal transporter-mediated disposition based on in vitro inputs, and verified using first-in-human data, indicated the key role of OATP-mediated hepatic uptake in the systematic and target-tissue exposure of PF-04991532. Mechanistic evaluation of the clinical data suggest reduced hepatic OATPs (~ 35%) and renal organic anion transporter (OAT)3 (80-90%) function with renal impairment. This study illustrates the adequacy and utility of the PBPK approach in assessing the impact of drug interactions and kidney dysfunction on transporter-mediated disposition., (© 2019 Pfizer Inc. Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Sebum plays important physiological roles in human skin. Excess sebum production contributes to the pathogenesis of acne vulgaris, and suppression of sebum production reduces acne incidence and severity. We demonstrate that sebum production in humans depends on local flux through the de novo lipogenesis (DNL) pathway within the sebocyte. About 80 to 85% of sebum palmitate (16:0) and sapienate (16:1n10) were derived from DNL, based on stable isotope labeling, much higher than the contribution of DNL to triglyceride palmitate in circulation (~20%), indicating a minor contribution by nonskin sources to sebum lipids. This dependence on local sebocyte DNL was not recapitulated in two widely used animal models of sebum production, Syrian hamsters and Göttingen minipigs. Confirming the importance of DNL for human sebum production, an acetyl-CoA carboxylase inhibitor, ACCi-1, dose-dependently suppressed DNL and blocked synthesis of fatty acids, triglycerides, and wax esters but not free sterols in human sebocytes in vitro. ACCi-1 dose-dependently suppressed facial sebum excretion by ~50% (placebo adjusted) in human individuals dosed orally for 2 weeks. Sebum triglycerides, wax esters, and free fatty acids were suppressed by ~66%, whereas non-DNL-dependent lipid species, cholesterol, and squalene were not reduced, confirming selective modulation of DNL-dependent lipids. Last, individuals with acne vulgaris exhibited increased sebum production rates relative to individuals with normal skin, with >80% of palmitate and sapienate derived from DNL. These findings highlight the importance of local sebocyte DNL for human skin sebaceous gland biology and illuminate a potentially exploitable therapeutic target for the treatment of acne vulgaris., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Acetylcarnitine has been identified as one of several urinary biomarkers indicative of radiation exposure in adult rhesus macaque monkeys (non-human primates, NHPs). Previous work has demonstrated an up-regulated dose-response profile in a balanced male/female NHP cohort. As a contribution toward the development of metabolomics-based radiation biodosimetry in human populations and other applications of acetylcarnitine screening, we have developed a quantitative, high-throughput method for the analysis of acetylcarnitine. We employed the Sciex SelexIon DMS-MS/MS QTRAP 5500 platform coupled to flow injection analysis (FIA), thereby allowing for fast analysis times of less than 0.5 minutes per injection with no chromatographic separation. Ethyl acetate is used as a DMS modifier to reduce matrix chemical background. We have measured NHP urinary acetylcarnitine from the male cohorts that were exposed to the following radiation levels: control, 2, 4, 6, 7, and 10 Gy. Biological variability, along with calibration accuracy of the FIA-DMS-MS/MS method, indicates LOQ of 20 μM, with observed biological levels on the order of 600 μM and control levels near 10 μM. There is an apparent onset of intensified response in the transition from 6 to 10 Gy. The results demonstrate that FIA-DMS-MS/MS is a rapid, quantitative technique that can be utilized for the analysis of urinary biomarker levels for radiation biodosimetry., (Copyright © 2018 John Wiley & Sons, Ltd.)

Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.

Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis and de novo lipogenesis. Since acetyl-CoA carboxylase (ACC) is at the junction of lipids synthesis and oxidative metabolic pathways, we investigated whether use of a dual ACC inhibitor would provide a potential therapy against certain lipogenic cancers. The impact of dual ACC1/ACC2 inhibition was investigated using a dual ACC1/ACC2 inhibitor as well as dual siRNA knock down on the cellular viability and metabolism of two glioblastoma multiform cancer cell lines, U87 and a more aggressive form, U87 EGFRvIII. We first demonstrated that while ACCi inhibited DNL in both cell lines, ACCi preferentially blunted the U87 EGFRvIII cellular proliferation capacity. Metabolically, chronic treatment with ACCi significantly upregulated U87 EGFRvIII cellular respiration and extracellular acidification rate, a marker of glycolytic activity, but impaired mitochondrial health by reducing maximal respiration and decreasing mitochondrial ATP production efficiency. Moreover, ACCi treatment altered the cellular lipids content and increased apoptotic caspase activity in U87 EGFRvIII cells. Collectively these data indicate that ACC inhibition, by reducing DNL and increasing cellular metabolic rate, may have therapeutic utility for the suppression of lipogenic tumor growth and warrants further investigation., Competing Interests: This study was supported by Pfizer Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Lysophospholipase-like 1 (LYPLAL1) is an uncharacterized metabolic serine hydrolase. Human genome-wide association studies link variants of the gene encoding this enzyme to fat distribution, waist-to-hip ratio, and nonalcoholic fatty liver disease. We describe the discovery of potent and selective covalent small-molecule inhibitors of LYPLAL1 and their use to investigate its role in hepatic metabolism. In hepatocytes, selective inhibition of LYPLAL1 increased glucose production supporting the inference that LYPLAL1 is a significant actor in hepatic metabolism. The results provide an example of how a selective chemical tool can contribute to evaluating a hypothetical target for therapeutic intervention, even in the absence of complete biochemical characterization.

Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.

The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.

A previous report from our laboratory disclosed the identification of PF-04991532 [(S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid] as a hepatoselective glucokinase activator for the treatment of type 2 diabetes mellitus. Lack of in vitro metabolic turnover in microsomes and hepatocytes from preclinical species and humans suggested that metabolism would be inconsequential as a clearance mechanism of PF-04991532 in vivo. Qualitative examination of human circulating metabolites using plasma samples from a 14-day multiple ascending dose clinical study, however, revealed a glucuronide (M1) and monohydroxylation products (M2a and M2b/M2c) whose abundances (based on UV integration) were greater than 10% of the total drug-related material. Based on this preliminary observation, mass balance/excretion studies were triggered in animals, which revealed that the majority of circulating radioactivity following the oral administration of [¹⁴C]PF-04991532 was attributed to an unchanged parent (>70% in rats and dogs). In contrast with the human circulatory metabolite profile, the monohydroxylated metabolites were not detected in circulation in either rats or dogs. Available mass spectral evidence suggested that M2a and M2b/M2c were diastereomers derived from cyclopentyl ring oxidation in PF-04991532. Because cyclopentyl ring hydroxylation on the C-2 and C-3 positions can generate eight possible diastereomers, it was possible that additional diastereomers may have also formed and would need to be resolved from the M2a and M2b/M2c peaks observed in the current chromatography conditions. In conclusion, the human metabolite scouting study in tandem with the animal mass balance study allowed early identification of PF-04991532 oxidative metabolites, which were not predicted by in vitro methods and may require additional scrutiny in the development phase of PF-04991532., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

The present article summarizes Metabolites in Safety Testing (MIST) studies on a glucokinase activator, N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319), which is under development for the treatment of type 2 diametes mellitus. Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N-Demethylation to metabolite M1 [N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100- and 300-mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Because M1 accounted for 65% of the drug-related material at steady state, an authentic standard was synthesized and used for comparison of steady-state exposures in humans and the 3-month safety studies in rats and dogs at the no-observed-adverse-effect level. Although circulating levels of M1 were very low in beagle dogs and female rats, adequate coverage was obtained in terms of total maximal plasma concentration (∼7.7× and 1.8×) and area under the plasma concentration-time curve (AUC; 3.6× and 0.8× AUC) relative to the 100- and 300-mg doses, respectively, in male rats. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319: EC50 = 0.17 μM; M1: EC50 = 4.69 μM). Furthermore, M1 did not inhibit major human P450 enzymes (IC50 > 30 μM), and was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling. Insights gained from this analysis should lead to a more efficient and focused development plan for fulfilling MIST requirements with PF-04937319., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Glucokinase (GK) is a key regulator of glucose homeostasis, and development of small molecule activators of this enzyme represents a promising new approach for the treatment of type 2 diabetes mellitus., Areas Covered: This manuscript reviews small molecule patent disclosures between late 2011 and February 2014 for both GK activators (GKAs) and GK-glucokinase regulatory protein (GK-GKRP) disruptors. The review is organized by company and structural class., Expert Opinion: The field of GKA research continues to progress, driven by research across many organizations. To date, > 20 candidates have entered clinical development with the most advanced in Phase II trials. Despite promising efficacy, a significant number of early candidates have been discontinued for various reasons including increased risk of hypoglycemia and lack of durability. Recent work in the field has focused on liver-selective activators, which have shown lower hypoglycemia risk, including the development of novel GK-GKRP disruptors that act to indirectly increase hepatic GK activity.

Glucokinase activators (GKAs) are being developed for the treatment of type 2 diabetes. The toxicity of 4 GKAs (PF-04279405, PF-04651887, piragliatin, and PF-04937319) was assessed in mice, rats, dogs, and/or monkeys. GKAs were administered for 2 to 8 weeks. Standard endpoints, glucose, and insulin were assessed. All compounds produced varying degrees of hypoglycemia in all species. Brain neuronal necrosis and/or peripheral neuropathy were observed with most compounds. These findings are consistent with literature reports linking hypoglycemia with nervous system effects. Arteriopathy, mainly of cardiac vessels, was observed at a low frequency in monkey and/or dog. Arteriopathy occurred only at doses that produced severe and prolonged periods of repeated hypoglycemia. Since this lesion occurred in multiple studies with structurally distinct GKAs, these results suggested arteriopathy was related to GKA pharmacology. The morphological characteristics of the arteriopathy were consistent with that produced by experimental catecholamine administration. We hypothesize that the prolonged periods of hypoglycemia resulted in increased local and/or systemic concentrations of catecholamines via a counterregulatory and/or stress-related mechanism. Alternatively, prolonged hypoglycemia may have resulted in endothelial dysfunction leading to arteriopathy. This risk can be managed in human patients in clinical studies by careful glucose monitoring and intervention to avoid prolonged episodes of hypoglycemia., (© 2014 by The Author(s).)

Hyperglycemia resulting from type 2 diabetes mellitus (T2DM) is the main cause of diabetic complications such as retinopathy and neuropathy. A reduction in hyperglycemia has been shown to prevent these associated complications supporting the importance of glucose control. Glucokinase converts glucose to glucose-6-phosphate and determines glucose flux into the β-cells and hepatocytes. Since activation of glucokinase in β-cells is associated with increased risk of hypoglycemia, we hypothesized that selectively activating hepatic glucokinase would reduce fasting and postprandial glucose with minimal risk of hypoglycemia. Previous studies have shown that hepatic glucokinase overexpression is able to restore glucose homeostasis in diabetic models; however, these overexpression experiments have also revealed that excessive increases in hepatic glucokinase activity may also cause hepatosteatosis. Herein we sought to evaluate whether liver specific pharmacological activation of hepatic glucokinase is an effective strategy to reduce hyperglycemia without causing adverse hepatic lipids changes. To test this hypothesis, we evaluated a hepatoselective glucokinase activator, PF-04991532, in Goto-Kakizaki rats. In these studies, PF-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the glucose infusion rate was increased approximately 5-fold with PF-04991532. This increase in glucose infusion can be partially attributed to the 60% reduction in endogenous glucose production. While PF-04991532 induced dose-dependent increases in plasma triglyceride concentrations it had no effect on hepatic triglyceride concentrations in Goto-Kakizaki rats. Interestingly, PF-04991532 decreased intracellular AMP concentrations and increased hepatic futile cycling. These data suggest that hepatoselective glucokinase activation may offer glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials.

Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties., (Published by Elsevier Ltd.)

Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: Type 2 diabetes mellitus (T2DM) represents a rapidly expanding healthcare challenge. There is a significant need for novel therapies to help patients achieve and maintain glycemic control in order to avoid the long-term microvascular and macrovascular complications associated with the disease. Small molecule allosteric activators of the glucokinase enzyme, an important regulator of glucose homeostasis, have emerged as a potential new class of therapeutics. Glucokinase activators have been shown to effectively lower fasting and postprandial glucose in T2DM patients; however, hypoglycemia emerged as a potential risk limiting their therapeutic potential. To mitigate this risk, recent efforts have focused on the design of liver-specific activators that seek to normalize hepatic glucose uptake and production without potentiating glucose-stimulated insulin secretion., Areas Covered: The article reviews the various drug discovery strategies that have emerged for the development of candidates that selectively activate glucokinase in the liver. Literature from 2000 to 2012 is surveyed including scientific publications, patent applications, conferences and clinical trials., Expert Opinion: Liver selective agents have proven to be an effective strategy for mitigating the hypoglycemia risk that has been historically associated with this mechanism. The ultimate therapeutic potential of this approach will depend on the results of longer patient studies which are currently being conducted with several clinical candidates. The discovery of these liver-specific activators has highlighted several challenges in the design of tissue-selective therapeutics, which will need to be overcome in the future.

The tissue distribution of a drug can have significant impact on both its efficacy and safety. As a consequence, selective tissue targeting has become an attractive approach for optimizing the window between efficacy and safety for drug targets that are ubiquitously expressed and important in key physiological processes. Given the liver's key role in metabolic regulation and the fact that it is the principal tissue affected by diseases such as hepatitis B and C viruses as well as hepatocellular carcinoma, designing drugs with hepatoselective distribution profiles is an important strategy in developing safe cardiovascular, metabolic, antiviral and oncology drug candidates. In this paper, we analyze a diverse set of compounds from four different projects within Pfizer that specifically pursued liver targeting strategies. A number of key in vitro and in vivo ADME endpoints were collected including in vivo tissue exposure, oral bioavailability, clearance in preclinical species and in vitro hepatic OATP uptake, in vitro rat liver microsomal stability, permeability, solubility, logD, and others. From this analysis, we determined a set of general structure-liver-selectivity guides for designing orally bioavailable, liver-targeted candidates using liver specific OATP transporters. The guidelines have been formulated using straightforward molecular descriptors and in vitro properties that medicinal chemists routinely optimize. Our analysis emphasizes the need to focus on a chemical space with balanced lipophilicity, high aqueous solubility and low passive permeability in order to achieve the desired hepatoselectivity while maintaining fraction absorbed.

Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

One gap in current patent-mining practice is the lack of tools to build SAR knowledge. Here, we report a novel technique that enabled us to derive useful SAR information from the exemplified structures of a series of patents. In our approach, exemplified chemical structures were extracted from patent documents. They were grouped into structural series based on similarity and binding mode, after which the R-group table was generated. By analyzing R-group usages over time, we were able to build insights into SAR of a structural series, even though the biological activities were not available.

In this review we highlight recently disclosed progress in the field of small-molecule activators of the human glucokinase enzyme. Several of the reported chemotypes possess structural features that diverge from known leads; some of these modifications appear to be specifically designed to modulate tissue selectivity or discrete parameters of enzyme function (e.g., S0.5 v Vmax). This review will inform the reader of the extent of continued effort being directed toward discovery of a first-in-class drug for Type II diabetes mellitus that functions through this target. Patents were selected from those published in December 2009 up to November 2011; foreign filings were translated where possible to understand the claims and biological techniques utilized to characterize the reported glucokinase activators. Overall, there appears to be a recent trend leading to reduced patent filings for small-molecule glucokinase activators. There are many possible explanations for this trend; however, it is likely that the field has reached maturity and that the downturn of new disclosures represents the transition of many of these programs to the clinic.

In this paper, we describe a lead transformation tool, NEAT (Novel and Electronically equivalent Aromatic Template), which can help identify novel aromatic rings that are estimated to have similar electrostatic potentials, dipoles, and hydrogen bonding capabilities to a query template; hence, they may offer similar bioactivity profiles. In this work, we built a comprehensive heteroaryl database, and precalculated high-level quantum mechanical (QM) properties, including electrostatic potential charges, hydrogen bonding ability, dipole moments, chemical reactivity, and othe properties. NEAT bioisosteric similarities are based on the electrostatic potential surface calculated by Brood, using the precalculated QM ESP charges and other QM properties. Compared with existing commercial lead transformation software, (1) NEAT is the only one that covers the comprehensive heteroaryl chemical space, and (2) NEAT offers a better characterization of novel aryl cores by using high-evel QM properties that are relevant to molecular interactions. NEAT provides unique value to medicinal chemists quickly exploring the largely uncharted aromatic chemical space, and one successful example of its application is discussed herein.

Human glucokinase (GK) is a principal regulating sensor of plasma glucose levels. Mutations that inactivate GK are linked to diabetes, and mutations that activate it are associated with hypoglycemia. Unique kinetic properties equip GK for its regulatory role: although it has weak basal affinity for glucose, positive cooperativity in its binding of glucose causes a rapid increase in catalytic activity when plasma glucose concentrations rise above euglycemic levels. In clinical trials, small molecule GK activators (GKAs) have been efficacious in lowering plasma glucose and enhancing glucose-stimulated insulin secretion, but they carry a risk of overly activating GK and causing hypoglycemia. The theoretical models proposed to date attribute the positive cooperativity of GK to the existence of distinct protein conformations that interconvert slowly and exhibit different affinities for glucose. Here we report the respective crystal structures of the catalytic complex of GK and of a GK-glucose complex in a wide open conformation. To assess conformations of GK in solution, we also carried out small angle x-ray scattering experiments. The results showed that glucose dose-dependently converts GK from an apo conformation to an active open conformation. Compared with wild type GK, activating mutants required notably lower concentrations of glucose to be converted to the active open conformation. GKAs decreased the level of glucose required for GK activation, and different compounds demonstrated distinct activation profiles. These results lead us to propose a modified mnemonic model to explain cooperativity in GK. Our findings may offer new approaches for designing GKAs with reduced hypoglycemic risk.

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR., (© 2012 American Chemical Society)

GK (glucokinase) is an enzyme central to glucose metabolism that displays positive co-operativity to substrate glucose. Small-molecule GKAs (GK activators) modulate GK catalytic activity and glucose affinity and are currently being pursued as a treatment for Type 2 diabetes. GK progress curves monitoring product formation are linear up to 1 mM glucose, but biphasic at 5 mM, with the transition from the lower initial velocity to the higher steady-state velocity being described by the rate constant kact. In the presence of a liver-specific GKA (compound A), progress curves at 1 mM glucose are similar to those at 5 mM, reflecting activation of GK by compound A. We show that GKRP (GK regulatory protein) is a slow tight-binding inhibitor of GK. Analysis of progress curves indicate that this inhibition is time dependent, with apparent initial and final Ki values being 113 and 12.8 nM respectively. When GK is pre-incubated with glucose and compound A, the inhibition observed by GKRP is time dependent, but independent of GKRP concentration, reflecting the GKA-controlled transition between closed and open GK conformations. These data are supported by cell-based imaging data from primary rat hepatocytes. This work characterizes the modulation of GK by a novel GKA that may enable the design of new and improved GKAs.

A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Introduction: Cardiovascular disease (CVD) is a leading cause of death worldwide and hypercholesterolemia, or elevated low-density lipoprotein cholesterol (LDL-C), is a key risk factor. The standard of care for treating hypercholesterolemia is the use of HMG-CoA reductase inhibitors, also known as statins, which block the rate-limiting step of cholesterol biosynthesis. In widespread clinical use, statins have proven safe and effective for both primary prevention of coronary heart disease and secondary prevention of coronary events., Areas Covered: This review summarizes the patent literature and advances in the discovery and development of new HMG-CoA reductase inhibitors from 2000 to 2010., Expert Opinion: The discovery of statins has had significant impact on reducing the worldwide burden of cardiovascular disease; nevertheless, the fact that heart disease remains a leading cause of death indicates that additional efforts are still needed. Using current statins, most patients at low and moderate risk of CVD reach recommended LDL-C targets, but a significant portion of patients in the high risk category fail to achieve optimal LDL-C targets. The potential introduction of novel statins with increased efficacy and tolerability profiles may represent an opportunity to further reduce the incidence of cardiovascular disease. Herein, I review the patent literature and examine the properties of several next generation statin clinical candidates.

Previous studies on the in vitro metabolism of 4-alkylsulfonyl-2-pyridone-based glucokinase activators revealed a facile, non-enzymatic displacement of the 4-alkylsulfonyl group by glutathione. In the present studies, a role for glutathione-S-transferases (GST) as catalysts in the desulfonylation reaction was demonstrated using a combination of human liver microsomes, human liver cytosol and human GSTs. The identification of a glutathione conjugate in circulation following intravenous administration of a candidate 4-methylsulfonyl-2-pyridone to rats confirmed the relevance of the in vitro findings., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A promising area of novel anti-diabetic therapy involves identification of small molecule activators of the glucokinase enzyme to reduce blood glucose and normalize glucose stimulated insulin secretion. Herein, we report the identification and optimization of a series of 4-sulfonyl-2-pyridone activators. The activators were evaluated for in vitro biochemical activation and pharmacokinetic properties. As part of these efforts, a unique metabolic liability of the 4-sulfonyl-2-pyridone ring system was identified wherein this heterocycle readily undergoes conjugation with glutathione under non-enzymatic conditions.

Coronary heart disease (CHD) is a leading cause of death in the US, and hypercholesterolemia is a key risk factor for this disease. The current standard of care for treating hypercholesterolemia is the use of HMG-CoA reductase inhibitors, also known as statins, which block the rate-limiting step of cholesterol biosynthesis. In widespread clinical use, statins have proven safe and effective for both primary prevention of CHD and secondary prevention of coronary events. Results from several recent clinical trials have demonstrated that increasingly aggressive cholesterol-lowering therapy might offer additional protection against CHD compared with less aggressive treatment standards. While higher doses of current statin therapies are capable of achieving these more aggressive treatment goals, in certain cases statin-induced myalgia, the muscle pain or weakness that sometimes accompanies high-dose statin therapy, limits patient compliance with a treatment regimen. To address this limitation, efforts have been undertaken to develop highly hepatoselective statins that are capable of delivering best-in-class efficacy with minimized risk of dose-limiting myalgia. In this review, the preclinical and early clinical data for these next generation statins are discussed.

Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC 50 = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a Delta H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.

The P2Y(1) and P2Y(12) purinergic receptors are responsible for mediating adenosine diphosphate (ADP) dependent platelet aggregation. Evidence from P2Y(1) knockout studies as well as from nucleotide-based small molecule P2Y(1) antagonists has suggested that the antagonism of this receptor may offer a novel and effective method for the treatment of thrombotic disorders. Herein, we report the identification and optimization of a series of non-nucleotide P2Y(1) antagonists that are potent and orally bioavailable.

Cholesterol absorption inhibition (CAI) represents an important treatment option for hypercholesterolemia. Herein, we report the design and evaluation of a series of substituted oxazolidinones as ligands for the Niemann Pick C1 Like 1 (NPC1L1) protein, a key mediator of cholesterol transport. Novel analogs were initially evaluated in a brush border membrane NPC1L1 binding assay; subsequently, promising compounds were evaluated in vivo for acute inhibition of cholesterol absorption. These studies identified analogs with low micromolar NPC1L1 binding affinity and acute in vivo efficacy of >50% absorption inhibition at 3mg/kg.

In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.

An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity.

In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia.

This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.

Using structure-based design, a novel series of conformationally restricted, pyrrole-based inhibitors of HMG-CoA reductase were discovered. Leading analogs demonstrated potent inhibition of cholesterol synthesis in both in vitro and in vivo models and may be useful for the treatment of hypercholesterolemia and related lipid disorders.