Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes.

Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments.

A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as , we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation.

Pharmacological AMPK activation induces transcriptional responses congruent to exercise in skeletal and cardiac muscle, adipose tissues and liver.

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry.

Hit-to-Lead Optimization and Discovery of 5-((5-([1,1'-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase.

AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging.

Dipeptidyl Peptidase 4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1α in Patients With Type 2 Diabetes.

Objective: Antihyperglycemic agents, such as empagliflozin, stimulate proximal tubular natriuresis and improve cardiovascular and renal outcomes in patients with type 2 diabetes. Because dipeptidyl peptidase 4 (DPP-4) inhibitors are used in combination with sodium-glucose cotransporter 2 (SGLT2) inhibitors, we examined whether and how sitagliptin modulates fractional sodium excretion and renal and systemic hemodynamic function.

Research Design And Methods: We studied 32 patients with type 2 diabetes in a prospective, double-blind, randomized, placebo-controlled trial.

The discovery of novel 5,6,5- and 5,5,6-tricyclic pyrrolidines as potent and selective DPP-4 inhibitors.

Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.

Structure-activity-relationship of amide and sulfonamide analogs of omarigliptin.

A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.

Measurement of catecholamines in rat and mini-pig plasma and urine by liquid chromatography-tandem mass spectrometry coupled with solid phase extraction.

A tandem mass spectrometry method combined with an ion-pair chromatographic separation after weak cation exchange solid phase sample extraction for epinephrine (E), norepinephrine (NE) and dopamine (DA) has been developed. Two surrogate matrixes for plasma and urine as well as stable isotope labeled internal standards were utilized for quantitation. The observed dynamic range of E, NE and DA was 0.

Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes.

In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.

Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors.

The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose.

A new class of prolylcarboxypeptidase inhibitors, part 2: the aminocyclopentanes.

A series of potent inhibitors of prolylcarboxypeptidase (PrCP) was developed by modifying a lead structure that was discovered by high-throughput screening. The tert-butyl pyrrolidine was replaced by an aminocyclopentane to reduce the metabolic liabilities of the original lead. The compounds demonstrated sub-nanomolar in vitro IC(50) values, minimal activity shifts in pure plasma and improved pharmacokinetics.

A new class of prolylcarboxypeptidase inhibitors, part 1: discovery and evaluation.

A new structural class of potent prolylcarboxypeptidase (PrCP) inhibitors was discovered by high-throughput screening. The series possesses a tractable SAR profile with sub-nanomolar in vitro IC(50) values. Compared to prior inhibitors, the new series demonstrated minimal activity shifts in pure plasma and complete ex vivo plasma target engagement in mouse plasma at the 20 h post-dose time point (po).

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.

Synthesis and evaluation of [(1R)-1-amino-2-(2,5-difluorophenyl)ethyl]cyclohexanes and 4-[(1R)-1-amino-2-(2,5-difluorophenyl)ethyl]piperidines as DPP-4 inhibitors.

A series of 4-amino cyclohexanes and 4-substituted piperidines were prepared and evaluated for inhibition of DPP-4. Analog 20q displayed both good DPP-4 potency and selectivity against other proteases, while derivative 20k displayed long half life and modest oral bioavailability in rat. The most potent analog, 3-(5-aminocarbonylpyridyl piperidine 53j, displayed excellent DPP-4 activity with good selectivity versus other proline enzymes.

Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors.

A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.

Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors.

The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.

Discovery of potent and selective dipeptidyl peptidase IV inhibitors derived from beta-aminoamides bearing subsituted triazolopiperazines.

A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice.

Imidazopiperidine amides as dipeptidyl peptidase IV inhibitors for the treatment of diabetes.

A series of substituted imidazopiperidine amides has been prepared and evaluated for inhibition of dipeptidyl peptidase IV (DPP-4). Substitution at the 1- and 3-positions produced increased selectivity for DPP-4 relative to DPP-8 and DPP-9. Compounds in this series had IC(50) values as low as 5.

4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV.

A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species.

Design, synthesis, and biological evaluation of triazolopiperazine-based beta-amino amides as potent, orally active dipeptidyl peptidase IV (DPP-4) inhibitors.

Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated.

Discovery of 3-aminopiperidines as potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitors.

Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.

Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate).

A series of beta-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the beta-aminoamide series, which ultimately led to the discovery of JANUVIA (sitagliptin phosphate, compound 1), are described.

Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin.

Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.