Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High†pH Dynamic Kinetic Reduction.

Described here is an efficient stereoselective synthesis of vibegron enabled by an enzymatic dynamic kinetic reduction that proceeds in a high-pH environment. To overcome enzyme performance limitations under these conditions, a ketoreductase was evolved by a computationally and structurally aided strategy to increase cofactor stability through tighter binding.

Discovery of benzamides as potent human ß3 adrenergic receptor agonists.

The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human ß3-adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was synthesized. From library synthesis and further optimization efforts, several structurally diverse reverse amides such as 24c and 24i were found to have excellent human ß3-adrenergic potency and good selectivity over the ß1 and ß2 receptors. In addition to human ß1, ß2, ß3 and hERG data, PK of selected compounds will be described.

Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective ß3 adrenergic receptor agonists for the treatment of overactive bladder.

A series of conformationally restricted acetanilides were synthesized and evaluated as ß3-adrenergic receptor agonists (ß3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine ß3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent ß3-AR mediated responses in a rat bladder hyperactivity model.

Asymmetric synthesis of cis-2,5-disubstituted pyrrolidine, the core scaffold of ß3-AR agonists.

A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of ß3-AR agonists is synthesized in 38% overall yield.

Synthesis and evaluation of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety as selective ß3-adrenergic receptor agonists.

In the search for potent and selective human ß3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against human ß3-, ß2-, and ß1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-yl)acetamide (4 g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the ß3-AR with functional selectivity over the ß1- and ß2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent model of diabetes.

Mirabegron, a ß3-adrenoceptor agonist for the potential treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder.

Mirabegron (YM-178), currently in development by Astellas Pharma Inc, is an orally active ß3-adrenoceptor (AR) agonist for the potential symptomatic treatment of overactive bladder (OAB). Mirabegron demonstrates nanomolar EC50 values against the human ß3-AR in biochemical assays with potent selectivity over the ß1- and ß2-ARs. Originally developed as a treatment for diabetes, the development of mirabegron was later refocused to OAB. Cystometric experiments in rats reported a reduction in resting intravesical pressure and contraction frequency in anesthetized rats, without any effect on the amplitude of micturition contraction. Mirabegron also reduced non-micturition bladder contractions in an awake rat model of bladder outlet obstruction. Top-line results from clinical trials to date indicate that mirabegron has been well tolerated with significant efficacy in reducing the number of incontinence episodes and mean micturition frequency in patients. Evidence of cytochrome P450 (CYP)2D6 inhibition in clinical trials highlighted a concern for pharmacokinetic interaction with other drugs that are CYP2D6 substrates, as confirmed by a rise in the pharmacokinetic parameters of desipramine with concomitant administration of mirabegron. Mirabegron exhibits a novel mode of action in targeting the ß3-AR for bladder relaxation, and the studies and trials conducted to date suggest mirabegron as a promising new treatment in the management of OAB symptoms, such as increased urinary urgency and frequency, and urgency incontinence.