1. Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans
- Author
-
Mark L. Lewis, Nick Edmunds, Stefan Sultana, Natalie M. Mount, Mark Ian Lansdell, Peter Wilson, Anne C. Heatherington, T. Bruce Brown, Alan Daniel Brown, Sarah Tweedy, David Hepworth, Julian Blagg, Cathryn Adams, Samantha Gaboardi, Kim Tang, Stevie Neal-Morgan, Andrew A. Calabrese, Neela Mistry, Maria Sudworth, David Sebastien Fradet, Neil Feeder, Val Gillon, Susan Cole, Steven W. Martin, Faye J. Quinton, Joanne Phipps, Scott Haughie, Denise J. Burring, Peter Stacey, Hugh Verrier, and Chris Wayman
- Subjects
Agonist ,Male ,Models, Molecular ,medicine.medical_specialty ,Pyrrolidines ,Sildenafil ,medicine.drug_class ,Administration, Sublingual ,Administration, Oral ,Biological Availability ,Biology ,Pharmacology ,In Vitro Techniques ,Crystallography, X-Ray ,chemistry.chemical_compound ,Structure-Activity Relationship ,Dogs ,Erectile Dysfunction ,Piperidines ,Oral administration ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor ,Administration, Intranasal ,Randomized Controlled Trials as Topic ,Clinical Trials, Phase I as Topic ,Stereoisomerism ,Rats ,Melanocortin 4 receptor ,Sexual dysfunction ,Endocrinology ,chemistry ,Hepatocytes ,Microsomes, Liver ,Molecular Medicine ,Receptor, Melanocortin, Type 4 ,Nasal administration ,Melanocortin ,medicine.symptom - 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.
- Published
- 2010