Discovery of Novel Indazole Derivatives as Orally Available β-Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects.

We previously discovered that indazole derivative 8 was a highly selective β-adrenergic receptor (β-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent β-AR agonist (EC = 18 nM) being inactive to β-, β-, and α-AR (β/β, β/β, and α/β > 556-fold).

Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β3-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects.

Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human β3-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant β3-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the α1A-AR (EC50 = 219 nM, selectivity: α1A/β3 = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for β3-AR agonistic activity versus α1A-AR agonistic activity.

Discovery of 2-(1H-indazol-1-yl)-thiazole derivatives as selective EP(1) receptor antagonists for treatment of overactive bladder by core structure replacement.

We have designed a series of potent EP1 receptor antagonists. These antagonists are a series of 2-(1H-indazol-1-yl)-thiazoles in which the core structure was replaced with pyrazole-phenyl groups. In preliminary conscious rat cystometry experiments, two representative candidates, 2 and 22, increased bladder capacity.

SAR-based optimization of 2-(1H-pyrazol-1-yl)-thiazole derivatives as highly potent EP1 receptor antagonists.

We describe a medicinal chemistry approach for generating a series of 2-(1H-pyrazol-1-yl)thiazoles as EP1 receptor antagonists. To improve the physicochemical properties of compound 1, we investigated its structure-activity relationships (SAR). Optimization of this lead compound provided small compound 25 which exhibited the best EP1 receptor antagonist activity and a good SAR profile.

Hit-to-lead optimization of 2-(1H-pyrazol-1-yl)-thiazole derivatives as a novel class of EP1 receptor antagonists.

We describe a medicinal chemistry approach to generate a series of 2-(1H-pyrazol-1-yl)thiazole compounds that act as selective EP1 receptor antagonists. The obtained results suggest that compound 12 provides the best EP1 receptor antagonist activity and demonstrates good oral pharmacokinetics.

A simple method to evaluate reactivity of acylglucuronides optimized for early stage drug discovery.

Drugs containing the carboxylic functional group can be metabolized to form acylglucuronides believed to cause idiosyncratic drug toxicity when the acylglucuronide is unstable. Recent studies have shown that the half-life of an acylglucuronide in phosphate buffer is the best means for classifying acylglucuronides into safe, warning, and withdrawn drugs. However, it is difficult to halt the late stage development of new chemical entities due to the instability of their acylglucuronides.