Philip A. Carpino

Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperidine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist.

We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) and functional assays (Ki = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.

Discovery of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (PF-514273), a novel, bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity.

We report the design, synthesis, and structure-activity relationships of novel bicyclic lactam-based cannabinoid type 1 (CB(1)) receptor antagonists. Members of these series are potent, selective antagonists in in vitro/in vivo efficacy models of CB(1) antagonism and exhibit robust oral activity in rodent models of food intake. These efforts led to the identification of 19d, which has been advanced to human clinical trials for weight management.

A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification

We report that 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), which behaves as a positive allosteric modulator at the glucagon-like peptide-1 receptor (GLP-1R), covalently modifies cysteines 347 and 438 in GLP-1R. C347, located in intracellular loop 3 of GLP-1R, is critical to the activity of BETP and a structurally distinct GLP-1R ago-allosteric modulator, N-(tert-butyl)-6,7-dichloro-3-(methylsulfonyl)quinoxalin-2-amine. We further show that substitution of cysteine for phenylalanine 345 in the glucagon receptor is sufficient to confer sensitivity to BETP.

Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs) : Discovery of capromorelin

Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.

Recent developments in ghrelin receptor (GHS-R1a) agonists and antagonists

The 28 amino acid polypeptide, ghrelin, is a novel neuroendocrine hormone synthesised primarily in the stomach. It stimulates growth hormone (GH) secretion, increases food intake and appetite and promotes body weight gain by decreasing fat mass metabolism, particularly in rodent models. The pharmacological properties of this peptide are mediated by the type 1a growth hormone secretagogue receptor (GHS-R1a), a G-protein-coupled receptor localised predominantly in the pituitary gland and hypothalamus. The discovery of new agents that either mimic or modulate the actions of ghrelin via the GHS-R1a has attracted considerable interest in recent years. Many peptidyl and peptidomimetic GHS-R1a agonists such as growth hormone-releasing peptides (GHRPs) and growth hormone secretagogues (GHSs) that stimulate GH secretion and increase plasma levels of insulin-like growth factor-1 (IGF-1) have been identified. First generation GHSs have undergone extensive clinical evaluation in humans, but have shown disappointing results in the treatment of diseases such as frailty, the age-related decline in body composition. Several of these compounds were found to increase adiposity in rodent models. Second generation dipeptidyl and third generation small molecule GHSs have recently been profiled in various animal models. A third generation of GHS with partial agonist activity at the GHS-R1a showed anabolic activity in rodent models, increasing fat-free (muscle) mass rather than fat mass. A few GHS-R1a receptor antagonists have been disclosed, although these compounds have exhibited poor selectivities or weak affinities for the receptor. Since endogenous ghrelin appears to play an important role in the long-term regulation of energy balance, GHS-R1a antagonists may be useful in the prevention of weight gain, following weight loss, or in the treatment of obesity, a pathological condition characterised by excess adiposity. This review describes the pharmacology of select ghrelin receptor modulators and highlights new ghrelin receptor agonists and antagonists that have appeared in the literature from 1999 – 2002.

Diabetes area participation analysis: a review of companies and targets described in the 2008 – 2010 patent literature

Importance of the field: Type 2 diabetes is a chronic disease characterized by the development of insulin resistance, impaired pancreatic β-cell function and, ultimately, hyperglycemia. The disease is highly associated with obesity and it is thought that the inappropriate deposition of lipid in tissues such as liver and muscle contributes to a reduction in insulin sensitivity which, in turn, places a burden on the β-cell to secrete more insulin to achieve normoglycemia. Over an extended period of time, this can result in β-cell failure and diminished glycemic control. When poorly managed, type 2 diabetes increases the risk of developing both microvascular and macrovascular complications, including retinopathy, nephropathy and coronary artery disease. The number of Americans with diabetes has approached 24 million in 2007 and the prevalence of the disease is projected to increase with the sedentary lifestyles and high caloric diets that are common today. First-line treatment for the disease involves lifestyle modifications and, if unsuccessful, pharmacotherapy to control symptoms. Anti-diabetic drugs belonging to several mechanistic classes are available (e.g., insulin secretagogues, insulin sensitizers, insulin mimetics and DPP IV inhibitors); however, many of these drugs lose their effectiveness over time, are not well-tolerated in some patients or may have suboptimal risk:benefit ratios. The search for new anti-diabetic drugs has continued to attract considerable interest from both academia and the pharmaceutical industry. Areas covered in this review: An analysis of 2008 – 2010 patent applications claiming diabetes as an indication has been undertaken. What the reader will gain: An understanding of: i) the pharmaceutical companies that have filed patent applications in the anti-diabetes area during 2008 – 2010; ii) the different pharmacological targets under investigation and the patent activity around such targets; iii) some of the targets in the research portfolios of selected companies; iv) chemical structures of compounds that modulate emerging targets and v) the pharmacological rationale underlying several targets with the largest patent counts. Take home message: Type 2 diabetes is a complex disease with many potential points of intervention for pharmacotherapy. A majority of anti-diabetic patent applications claim chemical matter for just eight targets which include five enzymes, a GPCR, a family of nuclear hormone receptors and a class of sodium-dependent glucose co-transporters (11β-HSD1, DGAT1, DPP IV, glucokinase, GPR119, PPAR-α, -δ, -γ, SGLT1 and SGLT2, and stearoyl-CoA desaturase 1 (SCD1)). The major pharmaceutical companies are all pursuing some combination of these top eight targets. Several companies stand out for the breadth of new targets under investigation (e.g., F. Hoffmann-La Roche, Merck & Co., Pfizer, Takeda Pharmaceuticals, Sanofi-Aventis).

Discovery and biological characterization of capromorelin analogues with extended half-lives

New tert-butyl, picolyl and fluorinated analogues of capromorelin (3), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma IGF-1 levels. Compounds 4c and 4d (ACD LogD values >or=2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED(50)s>10 mg/kg). A less lipophilic derivative 4 (ACD LogD=1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty.

Design of a Potent CB1 Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents

Antagonism of cannabinoid-1 (CB1) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB1-mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB1 receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure-activity-relationship analysis of a novel bicyclic scaffold (3) that exhibits potent CB1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB1 receptor antagonists.

Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor.

The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.

Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)

The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.