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Based on 3-phenylpropionamides, a series of 3-arylpyrrolidine-2-carboxamide derivatives was designed and synthesized to study the effect of cyclizations as melanocortin-4 receptor ligands. It was found that the 2R,3R-pyrrolidine isomer possessed the most potent affinity among the four stereoisomers.

Piperazinebenzylamine derivatives from trans-4-(4-chlorophenyl)tetrahydrothiophene-3-carboxylic acid 6 and its S-oxide 7 and sulfone 8, and the tetrahydrofuran 9 and its two regioisomers 11 and 13 were synthesized and studied for their binding affinities at the human melanocortin-4 receptor. These five-membered ring constrained compounds possessed similar or lower potency compared to the acyclic analogs.

A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.

A series of trans-N-alkyl-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanemethylamines was synthesized and characterized for binding and function at the melanocortin-4 receptor (MC4R), and several potent benzylamine derivatives were identified. Compound 18 v was found to bind MC4R with potent affinity (K(i)=0.5 nM) and high selectivity over the other melanocortin subtypes and behaved as a functional antagonist (IC(50)=48 nM).

A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats.

A series of pyrrolidinones derived from phenylalaninepiperazines were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor. In addition to their high binding affinities, these compounds displayed high functional potencies. 12a had a K(i) of 0.94 nM in binding and IC(50) of 21 nM in functional activity. 12a also demonstrated efficacy in a mouse cachexia model.

A series of pyrrolidine derivatives were synthesized and characterized as potent agonists of the human melanocortin-4 receptor. For example, 28c had a K(i) of 13 nM in binding affinity and EC(50) of 6.9 nM in agonist potency with an intrinsic activity of 100% of the endogenous ligand alpha-MSH.

A series of alpha-benzylpropionylpiperazines were synthesized and tested as antagonists of the melanocortin-4 receptor. In addition to its high potency and selectivity, R-11a had desirable pharmacokinetic properties including high brain penetration in mice.

A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the alpha-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability.

A series of 2-pyridinylpiperazines derived from beta-Ala-(2,4-Cl)Phe dipeptide was synthesized for the study of their SARs and possible interactions with the MC4 receptor. Compounds such as 11k (Ki=6.5 nM) possessed high potency.

The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period.

A series of cyclohexylpiperazines was synthesized as potent and selective antagonists of the human MC4 receptor. Compound 14t displayed binding affinity (Ki) of 4.2 and 1100 nM at MC4R and MC3R, respectively.

SAR studies on a series of piperazinebenzenes directed toward the human melanocortin-4 receptor resulted in potent MC4R agonists. Replacement of the triazole moiety of an initial lead 4 by a basic nitrogen baring a lipophilic side-chain increased the binding affinities of these compounds. Analogs bearing an additional hetero-atom in the side-chain possessed good agonist potency. Thus, 11h had a Ki of 11 nM, and 13g exhibited an EC50 of 3.8 nM and a Ki of 6.4 nM.