This paper details the discovery and characterization of GSK345931 (
7i) from the lead compound
4.
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the ...EP
1 receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative
4 which displayed molecular weight of 414.9
g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound
7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9
g/mol). In addition,
7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
P2Y receptors have been reported to modulate gastrointestinal functions. The newest family member is the nucleotide-sugar receptor P2Y... P2ry14 mRNA was detected throughout the rat gut, with the ...highest level being in the forestomach. We investigated the role of the receptor in stomach motility using cognate agonists and knockout (KO) mice. In rat isolated forestomach, 100 ...M UDP-glucose and 100 ...M UDP-galactose both increased the baseline muscle tension (BMT) by 6.2 ± 0.6 and 1.6 ± 0.6 mN (P < 0.05, n = 3- 4), respectively, and the amplitude of contractions during electrical field stimulation (EFS) by 3.7 ± 1.7 and 4.3 ± 2.5 mN (P < 0.05, n = 3-4), respectively. In forestomach from wild-type (WT) mice, 100 ...M UDP-glucose increased the BMT by 1.0 ± 0.1 mN (P <0.05, n = 6) but this effect was lost in the KO mice (change of -0.1 ± 0.1 mN, n = 6). The 100 ...M UDP-glucose also increased the contraction amplitude during EFS in this tissue from the WT animals (0.9 ± 0.4 mN, P < 0.05, n = 6) but not from the KO mice (0.0 ± 0.2 mN, n = 6). In vivo, UDP-glucose at 2,000 mg/kg ip reduced gastric emptying in rats by 49.7% (P < 0.05, n = 4-6) and in WT and KO mice by 56.1 and 66.2%, respectively (P < 0.05, n = 7-10) vs. saline-treated control animals. There was no significant difference in gastric emptying between WT and KO animals receiving either saline or D-glucose. These results demonstrate a novel function of the P2Y... receptor associated with contractility in the rodent stomach that does not lead to altered gastric emptying after receptor deletion and an ability of UDP-glucose to delay gastric emptying without involving the P2Y... receptor. (ProQuest: ... denotes formulae/symbols omitted.)
P2Y receptors have been reported to modulate gastrointestinal functions. The newest family member is the nucleotide-sugar receptor P2Y
14
. P2ry14 mRNA was detected throughout the rat gut, with the ...highest level being in the forestomach. We investigated the role of the receptor in stomach motility using cognate agonists and knockout (KO) mice. In rat isolated forestomach, 100 μM UDP-glucose and 100 μM UDP-galactose both increased the baseline muscle tension (BMT) by 6.2 ± 0.6 and 1.6 ± 0.6 mN ( P < 0.05, n = 3–4), respectively, and the amplitude of contractions during electrical field stimulation (EFS) by 3.7 ± 1.7 and 4.3 ± 2.5 mN ( P < 0.05, n = 3–4), respectively. In forestomach from wild-type (WT) mice, 100 μM UDP-glucose increased the BMT by 1.0 ± 0.1 mN ( P <0.05, n = 6) but this effect was lost in the KO mice (change of −0.1 ± 0.1 mN, n = 6). The 100 μM UDP-glucose also increased the contraction amplitude during EFS in this tissue from the WT animals (0.9 ± 0.4 mN, P < 0.05, n = 6) but not from the KO mice (0.0 ± 0.2 mN, n = 6). In vivo, UDP-glucose at 2,000 mg/kg ip reduced gastric emptying in rats by 49.7% ( P < 0.05, n = 4–6) and in WT and KO mice by 56.1 and 66.2%, respectively ( P < 0.05, n = 7–10) vs. saline-treated control animals. There was no significant difference in gastric emptying between WT and KO animals receiving either saline or d-glucose. These results demonstrate a novel function of the P2Y
14
receptor associated with contractility in the rodent stomach that does not lead to altered gastric emptying after receptor deletion and an ability of UDP-glucose to delay gastric emptying without involving the P2Y
14
receptor.
Although the beta(3)-adrenoceptor (AR) has been suggested to be involved in regulation of gut motility and visceral algesia, the precise mechanisms have been unknown. beta(3)-AR has been postulated ...to have a nonneuronal expression, being initially characterized in adipocytes and subsequently in the smooth muscle. We aimed to investigate the expression of beta(3)-AR in human enteric nervous system and its role in motility and visceral algesia.
The expression of beta(3)-AR in human colon myenteric and submucosal plexus was investigated using immunohistochemistry. The effects of a beta(3)-AR agonist on nerve-evoked and carbachol-induced contractions as well as somatostatin release were investigated in strips of human colon. The effect of an agonist on diarrhea and visceral pain was investigated in vivo in rat models.
beta(3)-AR is expressed in cholinergic neurons in the myenteric plexus and submucosal plexus of human colon. Activation of beta(3)-AR causes the release of somatostatin from human isolated colon. In a rat model of visceral pain, beta(3)-AR agonist elicits somatostatin-dependent visceral analgesia. beta(3)-AR agonists inhibit cholinergically mediated muscle contraction of the human colon, as well as chemically induced diarrhea in vivo in a rat model.
This is the first demonstration of expression of beta(3)-AR in the enteric nervous system. Activation of these receptors results in inhibition of cholinergic contractions and enhanced release of somatostatin, which may lead to visceral analgesia and inhibition of diarrhea. Therefore, beta(3)-AR could be a novel therapeutic target for functional gastrointestinal disorders.
A high-throughput screen targeting the EP sub(1) receptor identified non- acidic glycine sulfonamide derivative 2a with a pK sub(i) of 6.2. Analogue synthesis allowed a thorough investigation of the ...structure-activity relationship (SAR) and led to a 100-fold increase in recombinant potency.
The discovery, synthesis, pharmacokinetic profile and structure–activity relationships of a novel series of non-acidic EP
1 receptor antagonists are described.
A high-throughput screen targeting the ...EP
1 receptor identified non-acidic glycine sulfonamide derivative
2a with a p
K
i of 6.2. Analogue synthesis allowed a thorough investigation of the structure–activity relationship (SAR) and led to a 100-fold increase in recombinant potency.