Discovery of a Selective Small-Molecule Melanocortin-4 Receptor Agonist with Efficacy in a Pilot Study of Sexual Dysfunction in Humans

Abstract

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

“…However, a clinical trial in 2009 indicated potent side effects including an increase in blood pressure with the use of the peptide agonist LY2112688 (Ac-DArg-c[Cys-Glu-His-DPhe-Arg-Trp-Cys]-NH 2 ) [25] and decreased the rate of MC4R-selective small molecule agonist development as anti-obesity treatments. The potential uses of MC4R agonists as pro-erectile agents or MC4R antagonists as weight gain therapeutics for cachexia patients have also been investigated [137-139]. …”

“…( 13 , Figure 3) [137]. A previous MC4R agonist developed by this group possessing a 4-alcohol on the phenylpiperidine ring suggested small flanking substitutions on the C3 and C5 position of the piperidine ring had a beneficial effect, and was the basis for their structure-activity relation study.…”

“…A previous MC4R agonist developed by this group possessing a 4-alcohol on the phenylpiperidine ring suggested small flanking substitutions on the C3 and C5 position of the piperidine ring had a beneficial effect, and was the basis for their structure-activity relation study. Probing substitutions on the aryl portion of the phenylpiperidine ring and substitution on the pyrrolidine nitrogen led to two compounds, a phenyl/ tert -butyl or 4-fluorophenyl/ tert -butyl substitution pattern possessing 12 and 18 nM agonist potency at the hMC4R and approximately 100-fold selectivity for this receptor [137]. The phenyl/ tert -butyl compound was advanced into a human trial for male erectile dysfunction.…”

“…The phenyl/ tert -butyl compound was advanced into a human trial for male erectile dysfunction. A 200 mg dose demonstrated similar efficacy to sildenafil and demonstrated a significant effect compared to the placebo control [137]. …”

Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner

“…Here, we investigated the effects of daily MTII and the more selective, small molecule MC4R agonist, PF446687 (Lansdell et al, 2010) injections during the first week of life on juvenile play and adult pair bonding in males and female prairie voles. We also assessed the impact of peripheral MTII on hypothalamic neuropeptide systems using the immediate early gene, early growth response factor-1, as a marker of neuronal activity.…”