Piperidine derivatives as nonprostanoid IP receptor agonists 2.

We searched for a strong and selective nonprostanoid IP agonist bearing piperidine and benzanilide moieties. Through optimization of substituents on the benzanilide moiety, the crucial part of the agonist, 43 (2-((1-(2-(N-(4-tolyl)benzo[d][1,3]dioxole-5-carboxamido)ethyl)piperidin-4-yl)oxy)acetic acid monohydrate monohydrochloride) was discovered and exhibited strong platelet aggregation inhibition (IC50=21nM) and 100-fold selectivity for IP receptor over other PG receptors. The systemic exposure level and bioavailability after oral administration of 43 were also good in dog.

Piperidine derivatives as nonprostanoid IP receptor agonists.

The discovery of a new class of nonprostanoid prostaglandin I2 receptor (IP receptor) agonists is reported. Among them, the unique piperidine derivative 31b (2-((1-(2-(N-(4-tolyl)benzamido)ethyl)piperidin-4-yl)oxy)acetic acid) was a good IP receptor agonist and was 50-fold more selective for the human IP receptor than for other human prostanoid receptors. This compound showed good pharmacokinetic properties in dog.

Indolylpiperidine derivatives as potent and selective α1B adrenoceptor antagonists.

A series of novel indolylpiperidine derivatives were synthesized, and their pharmacological profiles were assessed at rat α1A and α1B adrenoceptors through in vitro binding studies. Compound 12 (2-(3-(4-(6-fluoro-1H-indol-3-yl)piperidin-1-yl)propyl)-1,2,3,4-tetrahydroisoquinoline) was a potent α1B adrenoceptor antagonist (Ki=0.61 nM) and was about 40-fold more selective for the α1B adrenoceptor than for the α1A adrenoceptor. In addition, useful structure-activity relationship information was acquired for further improving selectivity for the α1B adrenoceptor.

Synthesis of novel IP agonists via N-aminoethyl cyclic amines prepared by decarboxylative ring-opening reactions.

An efficient synthesis of a highly potent and selective IP (PGI(2) receptor) agonist that is not structurally analogous to PGI(2) is described. This synthesis is accomplished through the following key steps: Nucleophilic ring-opening of 3-(4-chlorophenyl)-oxazolidin-2-one prepared by a one-pot procedure with 4-piperidinol and selective O-alkylation of 1-(2-(4-chlorophenylamino)ethyl)piperidin-4-ol. The obtained compound is a potent and selective IP agonist displaying a long duration of action.

Efficient synthesis of a novel m-phenylene derivative as a selective EP4 agonist inducing follicular growth and maturation in the ovary.

An efficient and straightforward synthesis of a novel m-phenylene derivative has been developed. The optically pure dibromo compound was selected as a starting material. Through a protocol involving the Prins reaction and two steps of the Horner-Wadsworth-Emmons reaction, the basic skeleton was constructed with appropriate alpha and omega side chains. The compound proved to be a highly selective EP(4) agonist and a possible drug candidate for maturation of the uterine cervix.

Design and synthesis of selective alpha1B adrenoceptor antagonists.

A series of novel indolylpiperidine derivatives were synthesized and assessed for their pharmacological profiles at alpha1 adrenoceptor subtypes by in vitro binding studies at rat alpha1A and alpha1B receptors. Compound 11 was a potent (Ki=0.63 nM) and selective (approximately 30-fold more selective for the alpha1B receptor than for the alpha1A receptor) alpha1B adrenoceptor antagonist.

Enhanced cAMP response of naturally occurring mutant of human beta3-adrenergic receptor.

We have examined the functional significance of the naturally occurring mutation at position 64 of human beta3-adrenergic receptor (beta3AR), which changes the amino acid from tryptophan to arginine (W64R-beta3AR). The affinities of betaAR agonists for W64R-beta3AR expressed in COS-7 cells were not significantly different from those for wild type beta3AR. When two receptors are expressed at various expression levels, and stimulated with CGP12177A, they showed essentially the same EC50 values and maximal responses. Overexpression of Gi and Go, or the treatment with pertussis toxin did not affect the agonist-induced cAMP response, suggesting that Gi and Go did not contribute to the beta3AR-induced cAMP response. However, the enhanced cAMP response was observed when W64R-beta3AR was coexpressed with the adenylyl cyclase type III isoform, and stimulated by CGP12177A and isoproterenol. These results indicate that the cAMP response of W64R-beta3AR can be enhanced under the particular condition that adenylyl cyclase type III was coexpressed.