Zhengxiang Gu

A mild and efficient method for the preparation of guanidines

Abstract A mild and efficient method for the preparation of guanidines by reaction of an acylated thiourea with an amine followed by removal of the acyl group(s) from the intermediate acylguanidine is reported.

BMS-180560, an insurmountable inhibitor of angiotensin II-stimulated responses: comparison with losartan and EXP3174

1 This study compares the activity of BMS‐180560 (2‐butyl‐4‐chloro‐1‐[[1‐[2‐(2H‐tetrazol‐5‐yl)phenyl]‐1H‐indol‐4‐yl]methyl]‐1H‐imidazole‐5‐carboxylic acid), an insurmountable angiotensin II (AII) receptor antagonist, with that of losartan and EXP3174 in functional and biochemical models of AII‐receptor activation. 2 BMS‐180560 selectively inhibited [125I]‐Sar1Ile8AII ([125I]SI‐AII) binding to rat aortic smooth muscle (RASM) cell and rat adrenal cortical AT1 receptors (Ki = 7.6 ± 1.2 and 18.4 ± 3.9 nm respectively) compared to adrenal cortical AT2 receptors (Ki = 37.6 ± 1.3 μm). The Ki values of BMS‐180560 and EXP3174, but not losartan, varied as a function of the BSA concentration used in the assays, indicating that the diacid drugs bound to albumin. 3 BMS‐180560 (3–300 nm) increased the KD of SI‐AII for RASM cell AT1 receptors. Only at high concentrations of BMS‐180560 (300 nm) were Bmax values decreased. 4 BMS‐180560 inhibited AII‐stimulated contraction of rabbit aorta with a calculated KB = 0.068 ± 0.048 nm and decreased maximal AII‐stimulated contraction at 1 nm BMS‐180560 by 75%. In the presence of 0.1% BSA, a higher KB value (5.2 ± 0.92 nm) was obtained. Losartan behaved as a competitive antagonist with a KB = 2.6 ± 0.13 nm. Contraction stimulated by endothelin‐1, noradrenaline, KC1, or the TXA2 receptor agonist U‐46619 were unaffected by BMS‐180560 (1 nm). 5 All stimulated the acidification rates of RASM cells as measured by a Cytosensor microphysiometer with an EC50 of 18 nm. Losartan (30 nm) shifted the AII concentration‐effect curves in a competitive manner whereas BMS‐180560 (0.01 and 0.1 nm) decreased the maximum responses by 60 and 75% respectively. Inhibition by losartan and BMS‐180560 could be reversed following washout although recovery took longer for BMS‐180560. 6 In [3H]‐myoinositol‐labelled RASM cells, losartan (30 and 200 nm), shifted the EC50 for AII‐stimulated [3H]‐inositol monophosphate formation to higher values, with no change in the maximal response. By contrast, EXP3174 (0.1 to 1 nm) decreased the maximal response in a concentration‐dependent manner (17–55%). BMS‐180560 (3 and 10 nm) increased the EC50 for AII and decreased the maximum response by 30 and 80% respectively. The inhibition by EXP3174 and BMS‐180560 could be reversed by inclusion of losartan (200 nm) indicating that the inhibition was not irreversible. 7 In conclusion, BMS‐180560 is a potent, specific, predominantly competitive, reversible AII receptor antagonist, which displays insurmountable receptor antagonism. At concentrations of BMS‐180560 which have no effect on receptor number, BMS‐180560 produced insurmountable antagonism of AII‐stimulated second messenger formation, extracellular acidification, and smooth muscle contraction.

Orally active prodrugs of quinoline-4-carboxylic acid angiotensin II receptor antagonists

Abstract Prodrug derivatization of a potent quinoline-4-carboxylic acid angiotensin II receptor antagonist was Undertaken as an approach to achieve improved oral activity. A dioxolenone carboxylic ester and an alkylated tetrazole prodrug both showed greater oral antihypertensive acivity in the salt-deplete spontaneously hypertensive rat and increased oral bioavailability relative to the parent compound.

Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

1,4-substituted indoles: a potent and selective class of angiostensin II receptor antagonists

The syntheses and pharmacological activity of a series of 1,4-substituted indoles which function as nonpeptidic antagonists of the angiotensin II (AII) receptor are described. Compounds in this series are orally active and demonstrate long lasting antihypertensive activity.

REDUCTION OF SITE-SPECIFIC CYP3A-MEDIATED METABOLISM FOR DUAL ANGIOTENSIN AND ENDOTHELIN RECEPTOR ANTAGONISTS IN VARIOUS IN VITRO SYSTEMS AND IN CYNOMOLGUS MONKEYS

2-{Butyryl-[2′-(4,5-dimethyl-isoxazol-3-ylsulfamoyl)-biphenyl-4-ylmethyl]-amino}-N-isopropyl-3-methyl-butyramide (BMS-1) is a potent dual acting angiotensin-1 and endothelin-A receptor antagonist. The compound was subject to rapid metabolic clearance in monkey and human liver microsomes and exhibited low systemic exposure and marked interanimal variability in cynomolgus monkeys after p.o. administration. The variability pattern was identical to that of midazolam given p.o. in the same monkeys, as measured by area under the curve and Cmax values, suggesting that CYP3A-mediated metabolism might play a role in the rapid clearance and observed interanimal variability. Subsequent in vitro metabolism studies using human liver microsomes and cDNA-expressed human cytochrome P450 (P450) enzymes revealed that BMS-1 was a CYP3A4 substrate and was not metabolized by other human P450 enzymes. Mass spectral and NMR analyses of key metabolites led to the identification of the dimethyl isoxazole group as a major metabolic soft spot for BMS-1. Replacement of the 4-methyl group on the isoxazole ring with halogens not only improved overall metabolic stability but also decreased CYP3A-mediated hydroxylation of the isoxazole 5-methyl group. As exemplified by 2-{butyryl-[2′-(4-fluoro-5-methyl-isoxazol-3-ylsulfamoyl)-biphenyl-4-ylmethyl]-amino}-N-isopropyl-3-methyl-butyramide (BMS-3), a fluorinated analog of BMS-1, the structural modification resulted in an increase in the systemic exposure relative to previous analogs and a dramatic reduction in interanimal variability in the monkeys after p.o. administration. In addition, BMS-3 could be metabolized by both CYP2C9 and CYP3A4, thus avoiding the reliance on a single P450 enzyme for metabolic clearance. Integration of results obtained from in vitro metabolism studies and in vivo pharmacokinetic evaluations enabled the modulation of site-specific CYP3A-mediated metabolism, yielding analogs with improved overall metabolic profiles.

Design and synthesis of nonpeptidal endothelin receptor antagonists based on the structure of a cyclic pentapeptide

Abstract A series of dibenzodiazepine-10-acetic acid derivatives were synthesized as prototypes to mimic the structural features of the cyclopentapeptide endothelin antagonist 1. Some of the analogs showed moderate affinity for both the ETA and ETB receptors.

Characterization of a novel and selective CB1 antagonist as a radioligand for receptor occupancy studies

Obesity remains a significant public health issue leading to Type II diabetes and cardiovascular disease. CB1 antagonists have been shown to suppress appetite and reduce body weight in animal models as well as in humans. Evaluation of pre-clinical CB1 antagonists to establish relationships between in vitro affinity and in vivo efficacy parameters are enhanced by ex vivo receptor occupancy data. Synthesis and biological evaluation of a novel and highly selective radiolabeled CB1 antagonist is described. The radioligand was used to conduct ex vivo receptor occupancy studies.

Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.