4-Heteroaryl Phthalazin-1(2H)-one Derivatives as Potent Melanin Concentrating Hormone Receptor 1 (MCH-R1) Antagonists

Obesity is a chronic disorder in which there is an imbalance between energy intake and expenditure. According to a recent World Health Organization (WHO) report, more than one billion of adults in world population are overweight, and 200 million of these individuals are clinically obese. Moreover, obesity has emerged as a major risk factor for several associated diseases including type 2 diabetes, dyslipidemia, coronary heart disease, stroke and certain cancers. Therefore, a significant need exists for the development of efficacious and safe anti-obesity therapeutic agents. Among many centrally-acting neuropeptides, the melanin concentrating hormone (MCH), a cyclic 19-amino acid polypeptide, has attracted considerable recent attention as a target for the treatment of obesity. MCH, which is expressed predominantly in the lateral hypothalamus of the brain, is known to be involved in both regulation of feeding and energy homeostasis. The effects of this peptide are mediated by two types of G protein-coupled receptors called MCH receptor 1 and 2 (MCH-R1 and MCH-R2). The results of previous genetic and pharmacological studies have demonstrated that MCH-R1 plays an important role in the control of food intake and body-weight. These findings suggest that this receptor is one of the most promising targets for the treatment of obesity. Indeed, numerous MCH-R1 antagonists have been found to display anti-obesity efficacy in diet-induced obesity (DIO) animal models. Although numerous pharmaceutical companies have devoted considerable efforts to develop pharmacophore derivatives of MCH-R1 antagonists as potential anti-obesity agents, few candidates have advanced to the phase 1 clinical stage owing to their unsuitable pharmacokinetic (PK) profiles and safety concerns. Previously, we demonstrated that the 4-aryl phthalazin1(2H)-one derivatives linked to 4-aryl piperidine moiety are potent MCH-R1 antagonists. An extensive structure-activity relationship (SAR) investigation, probing the effects of substituents on the C-4 phenyl group of phthalazin-1(2H)one, led to the identification of the highly potent 3,4difluorophenyl derivative 1 (Figure 1), which was found to exhibit a high binding affinity to MCH-R1 (IC50 = 1 nM). In a continuing effort aimed at the development of potent MCH-R1 antagonists as anti-obesity agents, we have explored substances in which the C-4 aryl group of the phthalazin-1(2H)-one is replaced by heteroaryl groups (Figure 1). We envisioned that this modification might not only lead to an improved pharmacokinetic profile but also to enhance physicochemical properties while maintaining MCH-R1 binding activity. Below, we describe the results of this study which have led to the synthesis, biological evaluation, and evaluation of the structure-activity relationships of a variety of 4-heteroaryl phthalazin-1(2H)-one derivatives. The general synthetic route employed for the preparation of 4-heteroaryl phthalazin-1(2H)-one derivatives 2 is outlined in Scheme 1. The target compounds 2 were prepared starting from 2-bromobenzoic acid in four-step sequences by utilizing simple synthetic manipulations. Specifically, lithiumhalogen exchange reaction of 2-bromobenzoic acid using excess n-butyllithium, followed by acylation with appropriate heteroaroyl esters, produced the corresponding 2-heteroaroyl substituted benzoic acids 3. The key 4-heteroaryl phthalazin-1(2H)-ones intermediates 4 were then generated by condensation of the keto acids 3 with hydrazine. N-