ABSTRACT
N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.
Subject(s)
Drug Discovery , Gastrointestinal Agents/pharmacology , Piperazines/pharmacology , Piperidines/pharmacology , Pyloric Antrum/drug effects , Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Animals , Dogs , Gastrointestinal Motility/drug effects , Humans , Muscle Contraction/drug effects , Piperazines/chemistry , Piperidines/chemistry , Pyloric Antrum/physiology , Rabbits , RatsABSTRACT
Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
Subject(s)
Carbon/chemistry , Pyridines/chemistry , Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Gastrins/chemistry , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Pyridines/chemical synthesis , Pyridines/pharmacology , Rabbits , Rats , Receptors, Gastrointestinal Hormone/chemistry , Receptors, Neuropeptide/chemistryABSTRACT
6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.
Subject(s)
Benzothiazoles/chemical synthesis , Chemistry, Pharmaceutical/methods , Niacinamide/analogs & derivatives , Niacinamide/chemical synthesis , TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/chemistry , Administration, Oral , Animals , Benzothiazoles/pharmacology , Capsaicin/chemistry , Cell Line , Drug Design , Guinea Pigs , Humans , Inflammation , Inhibitory Concentration 50 , Models, Chemical , Niacinamide/chemistry , Niacinamide/pharmacology , RatsABSTRACT
Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
