In this work, two reliable aqueous solubility models, ASMS (aqueous solubility based on molecular surface) and ASMS-LOGP (aqueous solubility based on molecular surface using ClogP as a descriptor), were constructed by using atom type classified solvent accessible surface areas and several molecular descriptors for a diverse data set of 1708 molecules. For ASMS (without using ClogP as a descriptor), the leave-oneout q 2 and root-mean-square error (RMSE) were 0.872 and 0.748 log unit, respectively. ASMS-LOGP was slightly better than ASMS (q 2 ) 0.886, RMSE ) 0.705). Both models were extensively validated by three cross-validation tests and encouraging predictability was achieved. High throughput aqueous solubility prediction was conducted for a number of data sets extracted from several widely used databases. We found that real drugs are about 20-fold more soluble than the so-called druglike molecules in the ZINC database, which have no violation of Lipinski's "Rule of 5" at all. Specifically, oral drugs are about 16-fold more soluble, while injection drugs are 50-60-fold more soluble. If the criterion of a molecule to be soluble is set to -5 log unit, about 85% of real drugs are predicted as soluble; in contrast only 50% of druglike molecules in ZINC are soluble. We concluded that the two models could be served as a rule in druglike analysis and an efficient filter in prioritizing compound libraries prior to high throughput screenings (HTS).

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) = 0.08 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%).

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.

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