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.
Subject(s)
Erectile Dysfunction/drug therapy , Piperidines/chemical synthesis , Pyrrolidines/chemical synthesis , Receptor, Melanocortin, Type 4/agonists , Administration, Intranasal , Administration, Oral , Administration, Sublingual , Animals , Biological Availability , Clinical Trials, Phase I as Topic , Crystallography, X-Ray , Dogs , Hepatocytes/metabolism , Humans , In Vitro Techniques , Male , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/pharmacokinetics , Piperidines/pharmacology , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Randomized Controlled Trials as Topic , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The design and synthesis of the first fluorophore-conjugated SGLT2 inhibitors is described. The mode of linking the fluorophore to the SGLT2 pharmacophore was found to be crucial in achieving optimum potency. Superior potency to phlorizin was provided by examples containing TAMRA, BODIPY, Cy3B and NBD fluorophores.
Subject(s)
Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacology , Sodium-Glucose Transporter 2 Inhibitors , Combinatorial Chemistry Techniques , Drug Design , Fluorescent Dyes/chemistry , Molecular Structure , Phlorhizin/pharmacologyABSTRACT
This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
Subject(s)
Dopamine Agonists/administration & dosage , Dopamine Agonists/chemical synthesis , Drug Design , Receptors, Dopamine D3/agonists , Administration, Intranasal , Animals , Crystallography, X-Ray , Dogs , Dopamine Agonists/chemistry , Dopamine Agonists/pharmacokinetics , Humans , Models, Molecular , Molecular Structure , Rats , Receptors, Dopamine D3/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of substituted glutaramides were synthesised using Candoxatrilat 1 as a lead and evaluated for potency against neutral endopeptidase (NEP) as a potential treatment for female sexual arousal disorder (FSAD). In this paper, we describe studies in which we were able to increase NEP activity substantially over the levels reported for previous compounds from this programme by appropriate substitution in both the P(1)(') and P(2)(') regions. Optimisation led to the 4-chlorophenpropylamide S-30 which was selected as a candidate for further study.
