Development and Regulatory Challenges for Peptide Therapeutics.

There has been an increased interest in and activity for the use of peptide therapeutics to treat a variety of human diseases. The number of peptide drugs entering clinical development and the market has increased significantly over the past decade despite inherent challenges of peptide therapeutic discovery, development, and patient-friendly delivery. Disparities in interpretation and application of existing regulatory guidances to innovative synthetic and conjugated peptide assets have resulted in challenges for both regulators and sponsors. The Symposium on Development and Regulatory Challenges for Peptide Therapeutics at the 40th Annual Meeting of the American College of Toxicology held in November of 2019 focused on the following specific topics: (1) peptide therapeutic progress and future directions, and approaches to discover, optimize, assess, and deliver combination peptide therapeutics for treatment of diseases; (2) toxicological considerations to advance peptide drug-device combination products for efficient development and optimal patient benefit and adherence; (3) industry and regulatory perspectives on the regulation of synthetic and conjugated peptide products, including exploration of regulatory classifications, interpretations, and application of the existing guidances International Council for Harmonisation (ICH) M3(R2) and ICH S6(R1) in determining nonclinical study recommendations; and (4) presentation of the 2016 Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee working group assessment of genotoxicity testing requirements. Perspectives were shared from industry and regulatory scientists working in the peptide therapeutics field followed by an open forum panel discussion to discuss questions drafted for the peptide therapeutics scientific community, which will be discussed in more detail.

Insights into the Chemical Discovery of Remifentanil.

Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8. Copyright 1991 American Chemical Society. Reprinted with permission.In an effort to discover a potent ultrashort-acting µ-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent µ-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for µ-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent µ agonists in vitro, but depending upon the alkyl ester substitution, the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The [structure-activity relationships] with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

Orbital apocenter is not a sufficient condition for HST/STIS detection of Europa's water vapor aurora.

We report far-ultraviolet observations of Jupiter's moon Europa taken by Space Telescope Imaging Spectrograph (STIS) of the Hubble Space Telescope (HST) in January and February 2014 to test the hypothesis that the discovery of a water vapor aurora in December 2012 by local hydrogen (H) and oxygen (O) emissions with the STIS originated from plume activity possibly correlated with Europa's distance from Jupiter through tidal stress variations. The 2014 observations were scheduled with Europa near the apocenter similar to the orbital position of its previous detection. Tensile stresses on south polar fractures are expected to be highest in this orbital phase, potentially maximizing the probability for plume activity. No local H and O emissions were detected in the new STIS images. In the south polar region where the emission surpluses were observed in 2012, the brightnesses are sufficiently low in the 2014 images to be consistent with any H2O abundance from (0-5)×10(15) cm(-2). Large high-latitude plumes should have been detectable by the STIS, independent of the observing conditions and geometry. Because electron excitation of water vapor remains the only viable explanation for the 2012 detection, the new observations indicate that although the same orbital position of Europa for plume activity may be a necessary condition, it is not a sufficient condition. However, the December 2012 detection of coincident HI Lyman-α and OI 1304-Å emission surpluses in an ∼200-km high region well separated above Europa's limb is a firm result and not invalidated by our 2014 STIS observations.

Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.

Stabilization of the disk around beta Pictoris by extremely carbon-rich gas.

The edge-on disk surrounding the nearby young star beta Pictoris is the archetype of 'debris disks', which are composed of dust and gas produced by collisions between--and evaporation of--planetesimals, analogues of Solar System comets and asteroids. These disks may provide insight into the formation and early evolution of terrestrial planets. Previous work on beta Pic concluded that the disk gas has roughly solar abundances of elements, but this poses a problem because such gas should rapidly be blown away from the star, contrary to observations showing a stable gas disk in keplerian rotation. Here we report the detection of singly and doubly ionized carbon (C II, C III) and neutral atomic oxygen (O I) gas in the beta Pic disk. Carbon is extremely overabundant relative to every other measured element. This appears to solve the problem of the stable gas disk, because the carbon overabundance should keep the gas disk in keplerian rotation. The overabundance may indicate that the gas is produced from material more carbon-rich than expected of Solar System analogues.

The Plasma Environment of Comet 67P/Churyumov-Gerasimenko.

The environment of a comet is a fascinating and unique laboratory to study plasma processes and the formation of structures such as shocks and discontinuities from electron scales to ion scales and above. The European Space Agency's Rosetta mission collected data for more than two years, from the rendezvous with comet 67P/Churyumov-Gerasimenko in August 2014 until the final touch-down of the spacecraft end of September 2016. This escort phase spanned a large arc of the comet's orbit around the Sun, including its perihelion and corresponding to heliocentric distances between 3.8 AU and 1.24 AU. The length of the active mission together with this span in heliocentric and cometocentric distances make the Rosetta data set unique and much richer than sets obtained with previous cometary probes. Here, we review the results from the Rosetta mission that pertain to the plasma environment. We detail all known sources and losses of the plasma and typical processes within it. The findings from in-situ plasma measurements are complemented by remote observations of emissions from the plasma. Overviews of the methods and instruments used in the study are given as well as a short review of the Rosetta mission. The long duration of the Rosetta mission provides the opportunity to better understand how the importance of these processes changes depending on parameters like the outgassing rate and the solar wind conditions. We discuss how the shape and existence of large scale structures depend on these parameters and how the plasma within different regions of the plasma environment can be characterised. We end with a non-exhaustive list of still open questions, as well as suggestions on how to answer them in the future.

A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs.

The toxicity of tenofovir alafenamide (TAF) hemifumarate (HF) was evaluated when administered by continuous subcutaneous (s.c.) infusion via an external infusion pump for 28 days to rats and dogs. The toxicokinetics of TAF and two metabolites, tenofovir (TFV) and tenofovir diphosphate (TFV-DP) were also evaluated. After administration of TAF HF in rats and dogs, primary systemic findings supported an inflammatory response that was considered minimal to mild. Gross pathology and histopathologic evaluation of tissue surrounding the s.c. infusion site revealed signs of inflammation, including edema, mass formation, fibrosis, and mononuclear cell inflammation in groups receiving ≥300 µg/kg/day in rats and ≥25 µg/day in dogs. Although these changes were observed in animals receiving vehicle, the severity was greater in animals receiving TAF HF. Changes in the local tissue were considered a TAF HF-mediated exacerbation of an inflammatory response to the presence of the catheter. In rats, systemic and local findings were considered not adverse due to their low severity and reversibility; therefore, the "no observed adverse effect level" (NOAEL) was set at 1,000 µg/kg/day. Because none of the systemic findings were related to systemic exposure to TAF, the systemic NOAEL was set at 250 µg/kg/day in dogs. Due to the severity of the observations noted, a NOAEL for local toxicity could not be established. Although these results might allow for exploration of tolerability and pharmacokinetics of s.c. administered TAF HF in humans, data suggest a local reaction may develop in humans at doses below a clinically relevant dose. IMPORTANCE Human immunodeficiency virus (HIV) infection continues to be a serious global human health issue, with ∼38 million people living with HIV worldwide at the end of 2019. HIV preexposure prophylaxis (PrEP) has introduced the use of antiretroviral therapies as another helpful tool for slowing the spread of HIV worldwide. One possible solution to the problem of inconsistent access and poor adherence to HIV PrEP therapies is the development of subcutaneous (s.c.) depots or s.c. implantable devices that continuously administer protective levels of an HIV PrEP therapy for weeks, months, or even years at a time. We evaluate here the toxicity of tenofovir alafenamide, a potent inhibitor or HIV replication, after continuous s.c. infusion in rats and dogs for HIV PrEP.

Tenofovir Alafenamide for HIV Prevention: Review of the Proceedings from the Gates Foundation Long-Acting TAF Product Development Meeting.

The ability to successfully develop a safe and effective vaccine for the prevention of HIV infection has proven challenging. Consequently, alternative approaches to HIV infection prevention have been pursued, and there have been a number of successes with differing levels of efficacy. At present, only two oral preexposure prophylaxis (PrEP) products are available, Truvada and Descovy. Descovy is a newer product not yet indicated in individuals at risk of HIV-1 infection from receptive vaginal sex, because it still needs to be evaluated in this population. A topical dapivirine vaginal ring is currently under regulatory review, and a long-acting (LA) injectable cabotegravir product shows strong promise. Although demonstrably effective, daily oral PrEP presents adherence challenges for many users, particularly adolescent girls and young women, key target populations. This limitation has triggered development efforts in LA HIV prevention options. This article reviews efforts supported by the Bill & Melinda Gates Foundation, as well as similar work by other groups, to identify and develop optimal LA HIV prevention products. Specifically, this article is a summary review of a meeting convened by the foundation in early 2020 that focused on the development of LA products designed for extended delivery of tenofovir alafenamide (TAF) for HIV prevention. The review broadly serves as technical guidance for preclinical development of LA HIV prevention products. The meeting examined the technical feasibility of multiple delivery technologies, in vivo pharmacokinetics, and safety of subcutaneous (SC) delivery of TAF in animal models. Ultimately, the foundation concluded that there are technologies available for long-term delivery of TAF. However, because of potentially limited efficacy and possible toxicity issues with SC delivery, the foundation will not continue investing in the development of LA, SC delivery of TAF products for HIV prevention.

A large population of 'Lyman-break' galaxies in a protocluster at redshift z approximately 4.1.

The most massive galaxies and the richest clusters are believed to have emerged from regions with the largest enhancements of mass density relative to the surrounding space. Distant radio galaxies may pinpoint the locations of the ancestors of rich clusters, because they are massive systems associated with 'overdensities' of galaxies that are bright in the Lyman-alpha line of hydrogen. A powerful technique for detecting high-redshift galaxies is to search for the characteristic 'Lyman break' feature in the galaxy colour, at wavelengths just shortwards of Lyalpha, which is due to absorption of radiation from the galaxy by the intervening intergalactic medium. Here we report multicolour imaging of the most distant candidate protocluster, TN J1338-1942 at a redshift z approximately 4.1. We find a large number of objects with the characteristic colours of galaxies at that redshift, and we show that this excess is concentrated around the targeted dominant radio galaxy. Our data therefore indicate that TN J1338-1942 is indeed the most distant cluster progenitor of a rich local cluster, and that galaxy clusters began forming when the Universe was only ten per cent of its present age.

Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1.

The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.

6-(4-chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin-concentrating hormone receptor 1 antagonist.

Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.

Povidone-iodine sclerotherapy is ineffective in the treatment of symptomatic renal cysts.

PURPOSE: To evaluate the efficacy of povidone-iodine sclerotherapy after percutaneous drainage of simple renal cysts in the treatment of symptomatic patients. PATIENTS AND METHODS: Sixteen patients with symptomatic renal cysts were treated by percutaneous drainage and injection of povidone-iodine solution. The cysts were drained by a nephrostomy tube catheter, and povidone- iodine injections were repeated every 24 hours for 3 days. All patients were followed up by ultrasound examination during a period ranging from 1 to 4 years (mean 1.8 years). RESULTS: Thirteen patients experienced recurrence of cysts, while complete resolution was observed in only three patients. Of the cysts that recurred, only partial resolution in cyst diameter was observed (from 3-10.5 cm to 2.4-8.6 cm). During the follow-up period, 12 of the 16 patients (75%) continued to have pain that necessitated additional treatments. CONCLUSION: Povidone-iodine sclerotherapy is followed by a high rate of recurrence and is therefore not indicated for the treatment of symptomatic simple renal cysts.

Quality guidelines for oral drug candidates: dose, solubility and lipophilicity.

In an attempt to seek increased understanding of compound attributes that influence successful drug pipeline progression, GlaxoSmithKline's portfolio of oral candidates was compared with reference sets of marketed oral drugs. The approach differs from other attrition studies by explicitly focusing on choosing 'the right compound' by applying relevant, experimentally derived properties. The analysis led to four proposed compound quality categories, created by combining specific criteria for three measures: dose, solubility and the property forecast index, a composite measure of lipophilicity using chromatographically determined LogD and aromaticity. The 'three properties' provide benchmarked guidelines for project teams to use when seeking and selecting clinical candidates, because they reflect the property distribution of marketed oral drugs.

Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys.

Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED(95) = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED(95)) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED(95) value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED(95) = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED(95) = 0.103 mg/kg), difluorosuccinate (27c; ED(95) = 0.056 mg/kg), and fluorofumarate (28a; ED(95) = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 microg/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine.

Herpes simplex virus type 2 seropositivity in a sexually transmitted disease clinic in Israel.

BACKGROUND: Seroepidemeliogic surveys have provided valuable information on the prevalence and incidence of herpes simplex virus-2 infection in general and in selected populations. OBJECTIVE: To review the reliability of traditional diagnostic approaches in herpes simplex virus-2 infection. METHODS: In this cross-sectional study, 472 patients attending a clinic for sexually transmitted disease in 1998-1999 were evaluated for HSV-2 infection through collection of epidemiologic and clinical data. HSV-2 infection was confirmed by the presence of specific viral glycoprotein, gG-2, antibody in sera. RESULTS: The seroprevalence of HSV-2 among clinic attendees was 9.33%. Of these attendees only 22% presented with or reported a history of typical vesicular lesions in the genital area. Infection rate was higher in patients with multiple sex partners (20.8% vs. 8.7%, P < or = 0.0023), in individuals aged 30 or older (12.6 vs. 6.4%, P = 0.03) and in the Israeli Jewish population as compared to the Israeli Arab population (11.1% vs. 2.4%, P < or = 0.01). Females with multiple sex partners exhibited higher rates of infection than did their male counterparts (50 vs. 16.1%, P < or = 0.0275). CONCLUSION: The findings support the need for HSV-2 serologic testing in patients presenting to STD clinics even when typical genital lesions are not evident but where risk factors for HSV-2 infection are identified.

Candida albicans colonization of dental plaque in elderly dysphagic patients.

BACKGROUND: Dysphagia is a common disorder among the elderly population. As many as 50% of nursing home residents suffer from dysphagia. It is important to identify patients at increased risk for colonization of dental and denture plaque by pathogenic organisms in order to prevent associated disease. OBJECTIVES: To quantify the prevalence and evaluate the effect of dental and denture plaque colonization by Candida albicans in hospitalized elderly dysphagic patients as a complication of stroke, as well as the effect of systemic antimicrobial therapy on C. albicans colonization in these patients. METHODS: We evaluated dysphagia and antibiotic therapy as risk factors for dental and denture plaque colonization by C. albicans in elderly stroke rehabilitating patients with dysphagia, as compared to elderly non-dysphagic stroke and non-stroke rehabilitating patients on days 0, 7 and 14 following admission to the Fliman Geriatric Rehabilitation Hospital. RESULTS: The risk of C. albicans colonization of dental plaque was greater in dysphagic patients than in those without dysphagia on day 0 (50% vs. 21%, P = 0.076), day 7 (58 vs. 15.2%, P = 0.008) and day 14 (58 vs. 15.2%, P = 0.08). Similarly, patients on antibiotic therapy were at greater risk for C. albicans colonization of dental plaque on day 0 (56 vs. 11%, P = 0.002), day 7 (44 vs. 14.8%, P = 0.04) and day 14 (39 vs. 19%, P = 0.18). The risk of C. albicans colonization of denture plaque as opposed to dental plaques in non-dysphagic patients was significantly greater on day 0 (45.7 vs. 21.2%, P = 0.03), day 7 (51.4 vs. 15.1%, P = 0.0016) and day 14 (54.3 vs. 15.1%, P = 0.0007). Dysphagia did not increase the risk of denture plaque colonization by C. albicans. CONCLUSIONS: Both dysphagia and antibiotic therapy are risk factors for C. albicans colonization of dental plaque, and although dysphagia does not significantly increase colonization of denture plaque, denture wearers are at greater risk of such colonization.

Transient water vapor at Europa's south pole.

In November and December 2012, the Hubble Space Telescope (HST) imaged Europa's ultraviolet emissions in the search for vapor plume activity. We report statistically significant coincident surpluses of hydrogen Lyman-α and oxygen OI 130.4-nanometer emissions above the southern hemisphere in December 2012. These emissions were persistently found in the same area over the 7 hours of the observation, suggesting atmospheric inhomogeneity; they are consistent with two 200-km-high plumes of water vapor with line-of-sight column densities of about 10(20) per square meter. Nondetection in November 2012 and in previous HST images from 1999 suggests varying plume activity that might depend on changing surface stresses based on Europa's orbital phases. The plume was present when Europa was near apocenter and was not detected close to its pericenter, in agreement with tidal modeling predictions.

Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies.

UNLABELLED: GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25-800 mg; n = 45) or multiple doses (100-600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼ five-fold compared with placebo, reaching peak concentrations of ∼ 50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼ 100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides. TRIAL REGISTRATION: Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621.

Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes.

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.