ABSTRACT
Laropiprant is a selective antagonist of the prostaglandin D(2) (PGD(2)) receptor subtype 1 (DP1). Three double-blind, randomized, placebo-controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose-proportional pharmacokinetics. Oral absorption is rapid (T(max)=0.8-2.0 h) and the terminal half-life is approximately 12-18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD(2)-induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off-target antagonist effects at the thromboxane A(2) receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg.
Subject(s)
Indoles/adverse effects , Indoles/pharmacokinetics , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Receptors, Prostaglandin/metabolism , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Headache/blood , Headache/chemically induced , Humans , Indoles/therapeutic use , Male , Middle AgedABSTRACT
Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with niacin-induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1), which may mediate niacin-induced vasodilation. The aim of this proof-of-concept study was to evaluate the effects of laropiprant (vs placebo) on niacin-induced cutaneous vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended-release (ER) niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging. Laropiprant was effective after multiple doses in reducing symptoms of flushing and attenuating the increased malar skin blood flow induced by ER niacin. In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of niacin-induced vasodilation.
Subject(s)
Indoles/therapeutic use , Niacin/adverse effects , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Vasodilation/drug effects , Vasodilator Agents/adverse effects , Adolescent , Adult , Aspirin/pharmacology , Cross-Over Studies , Delayed-Action Preparations , Dose-Response Relationship, Drug , Female , Humans , Indoles/administration & dosage , Indoles/adverse effects , Male , Middle Aged , Niacin/administration & dosage , Regional Blood Flow , Skin/blood supply , Vasodilator Agents/administration & dosageABSTRACT
Apicidin, a natural product recently isolated at Merck, inhibits both mammalian and protozoan histone deacetylases (HDACs). The conversion of apicidin, a nanomolar inhibitor of HDACs, into a series of side-chain analogues that display picomolar enzyme affinity is described within this structure-activity study.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Histone Deacetylase Inhibitors , Peptides, Cyclic/pharmacology , Animals , Antiprotozoal Agents/pharmacology , Biological Factors/pharmacology , Cattle , Cell Line , Combinatorial Chemistry Techniques , Eimeria tenella/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fusarium/chemistry , HeLa Cells , Humans , Microbial Sensitivity Tests , Peptides, Cyclic/chemical synthesis , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
Recently isolated at Merck, apicidin inhibits both mammalian and protozoan histone deacetylases (HDACs). The conversion of apicidin, a nonselective nanomolar inhibitor of HDACs, into a series of picomolar indole-modified and parasite-selective tryptophan-replacement analogues is described within this structure-activity study.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Histone Deacetylase Inhibitors , Peptides, Cyclic/pharmacology , Animals , Antiprotozoal Agents/pharmacology , Biological Factors/pharmacology , Cattle , Cell Division/drug effects , Cell Line , Combinatorial Chemistry Techniques , Eimeria tenella/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fusarium/chemistry , HeLa Cells , Humans , Indoles/chemistry , Microbial Sensitivity Tests , Peptides, Cyclic/chemical synthesis , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Tryptophan/chemistryABSTRACT
A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L -isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.
