Showing papers by "Junmei Wang published in 2004"

Development and testing of a general amber force field.

Abstract: We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 A, which is comparable to that of the Tripos 5.2 force field (0.25 A) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 A, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 A and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 A and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching.

Discovery, modeling, and human pharmacokinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist.

Abstract: Sitaxsentan (1) (Wu et al J Med Chem 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al AHA Scientific Sessions 2000) In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al Am J Respir Crit Care Med 2004, 169, 441) We have since reported on our efforts in generating follow-up compounds (Wu et al J Med Chem 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al J Med Chem 2001, 44, 1211) Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (approximately 100%) in rats, high potency (ET(A) IC(50) = 008 nM), and optimal ET(A)/ET(B) selectivity (441 000-fold) Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%)

Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists

Abstract: The present invention relates to urotensin II receptor antagonists, pharmaceutical compositions containing them and their use.

Phenylenediamine urotensin-II receptor antagonists and CCR-9 antagonists

Abstract: The present invention relates to urotensin II receptor antagonists, CCR-9 antagonists, pharmaceutical compositions containing them and their use.

Pyridine, pyrimidine, quinoline, quinazoline et naphtalene, antagonistes du recepteur de l'urotensine ii

Abstract: La presente invention concerne des antagonistes du recepteur de l'urotensine II, des compositions pharmaceutiques contenant ces antagonistes, et leur utilisation.

CCR-9 antagonists

Abstract: The present invention relates to CCR-9 antagonists, pharmaceutical compositions containing them and their use.