Dong-Ming Shen

Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core.

A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.

A survey of small molecule glucagon receptor antagonists from recent patents (2006 – 2010)

Introduction: The ever increasing prevalence of type 2 diabetes mellitus (T2DM) in the developed and developing nations calls for the introduction of new and more effective treatments. Glucagon receptor (GCGR) antagonists are highly validated in preclinical models of T2DM and thus have the potential to be developed as a new therapy. Small molecule GCGR antagonists have been an active area of research since the 1990s. As evidenced from the number of patents and laboratories involved, these efforts have accelerated during the last decade. Areas covered: During the period 2006 – 2010, there were numerous patent publications from several laboratories claiming the discovery of novel small molecule GCGR antagonists. Herein, we present our interpretation of these new patent publications as well as follow-up disclosures appearing in the peer-reviewed literature. This paper provides an up-to-date overview of the field of small molecule GCGR antagonism as a potential treatment for T2DM. Attempts were made wherever possible to identify preferred or representative compounds from the patent applications reviewed. In vitro and in vivo data are also discussed where they were disclosed. Expert opinion: The novel small molecule GCGR antagonists reviewed here represent many diverse structural motifs. Some molecules are very potent antagonists of the GCGR in in vitro assays with acceptable selectivity. Some have intriguing in vivo activity in models of T2DM in a variety of preclinical species. It is to be hoped that clinical developments following these preclinical discoveries might result in a long-awaited new treatment for T2DM.

Mineralocorticoid receptor antagonists

With an increasingly aging population, the need for effective treatment of cardiovascular diseases (eg, heart failure, hypertension, and ischemic heart disease) cannot be overemphasized. The vital importance of mineralocorticoid receptor antagonists for treating cardiovascular conditions has only been appreciated in the last decade. The re-emergence of mineralocorticoid receptor antagonists has provided clinicians with an important tool towards complete blockade of the reninangiotensin-aldosterone axis.

Selective, direct activation of high-conductance, calcium-activated potassium channels causes smooth muscle relaxation.

High-conductance calcium-activated potassium (Maxi-K) channels are present in smooth muscle where they regulate tone. Activation of Maxi-K channels causes smooth muscle hyperpolarization and shortening of action-potential duration, which would limit calcium entry through voltage-dependent calcium channels leading to relaxation. Although Maxi-K channels appear to indirectly mediate the relaxant effects of a number of agents, activators that bind directly to the channel with appropriate potency and pharmacological properties useful for proof-of-concept studies are not available. Most agents identified to date display significant polypharmacy that severely compromises interpretation of experimental data. In the present study, a high-throughput, functional, cell-based assay for identifying Maxi-K channel agonists was established and used to screen a large sample collection (>1.6 million compounds). On the basis of potency and selectivity, a family of tetrahydroquinolines was further characterized. Medicinal chemistry efforts afforded identification of compound X, from which its two enantiomers, Y and Z, were resolved. In in vitro assays, Z is more potent than Y as a channel activator. The same profile is observed in tissues where the ability of either agent to relax precontracted smooth muscles, via a potassium channel-dependent mechanism, is demonstrated. These data, taken together, suggest that direct activation of Maxi-K channels represents a mechanism to be explored for the potential treatment of a number of diseases associated with smooth muscle hyperexcitability.

Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors

A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC(50)s were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight loss and food intake in an eDIO mouse model and the results will be discussed.

Design, Synthesis, and Evaluation of Conformationally Restricted Acetanilides as Potent and Selective β3 Adrenergic Receptor Agonists for the Treatment of Overactive Bladder

A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-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 β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.

Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder.

The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.

The discovery of non-benzimidazole and brain-penetrant prolylcarboxypeptidase inhibitors.

Novel prolylcarboxypeptidase (PrCP) inhibitors with nanomolar IC(50) values were prepared by replacing the previously described dichlorobenzimidazole-substituted pyrrolidine amides with a variety of substituted benzylamine amides. In contrast to prior series, the compounds demonstrated minimal inhibition shift in whole serum and minimal recognition by P-glycoprotein (P-gp) efflux transporters. The compounds were also cell permeable and demonstrated in vivo brain exposure. The in vivo effect of compound (S)-6e on weight loss in an established diet-induced obesity (eDIO) mouse model was studied.

Peptidomic profiling of human cerebrospinal fluid identifies YPRPIHPA as a novel substrate for prolylcarboxypeptidase

Prolylcarboxypeptidase (PRCP) is a serine protease that catalyzes the cleavage of C‐terminal amino acids linked to proline in peptides. It is ubiquitously expressed and is involved in regulating blood pressure, proliferation, inflammation, angiogenesis, and weight maintenance. To identify the candidate proximal target engagement markers for PRCP inhibition in the central nervous system, we profiled the peptidome of human cerebrospinal fluid to look for PRCP substrates using a MS‐based in vitro substrate profiling assay. These experiments identified a single peptide, with the sequence YPRPIHPA, as a novel substrate for PRCP in human cerebrospinal fluid. The peptide YPRPIHPA is from the extracellular portion of human endothelin B receptor‐like protein 2.

Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.