Search

Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Novel tricyclic indole-3-carboxamides were synthesized as structurally restricted analogs of bicyclic indoles, and found to be potent CB1 cannabinoid receptor agonists. The CB1 agonist activity depended on the absolute configuration of the chiral center of the tricyclic ring. The preferred enantiomer was more potent than the structurally unconstrained lead compound. Structure-activity relationships in the amide side chain of the indole C-3 position were also investigated., (2010 Elsevier Ltd. All rights reserved.)

A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified.

1. The pharmacological and biochemical effects of a novel cardiotonic agent, Org10325 have been studied in isolated cardiac and vascular tissue preparations. 2. Org10325 produced concentration-dependent (0.15-4.8 mM) positive inotropic, positive chronotropic and vascular relaxant responses in rabbit isolated papillary, atrial and aortic preparations, respectively. The maximal chronotropic effect (45%) was significantly less than the isoprenaline maximum. The inotropic effects of Org10325 were not modified by alpha- or beta-adrenoceptor blockade or by pretreatment with reserpine. Org10325 was at least 23 times more potent at relaxing aortic strips pre-contracted with phenylephrine than with KCl. 3. Org10325 (74 microM) potentiated (10-14 fold) the positive inotropic effects of isoprenaline in rabbit isolated papillary muscles. Carbachol inhibited the positive inotropic effect of Org10325. Both the positive inotropic and vasorelaxant effects of Org10325 were accompanied by increases in cyclic AMP but not cyclic GMP. 4. In rat perfused heart preparation Org10325 increased phosphorylase a, cyclic AMP-dependent protein kinase activities and stimulated phosphorylation of contractile proteins (troponin-I and C-protein). 5. Org10325 selectively inhibited the cyclic AMP hydrolytic activity of cyclic AMP high affinity cyclic nucleotide phosphodiesterase (PDE) isoenzymes, PDE III (IC50 65 microM) and PDE IV (IC50 71 microM), from rabbit cardiac ventricle. Weak inhibition (IC50 greater than 250 microM) of PDE I and PDE II was observed. 6. The results show that the cardiac and vascular effects of Org10325 are mediated by an increase in cellular cyclic AMP due to inhibition of PDE III and PDE IV activities. However, in contrast to other PDE-inhibitors OrglO325 produced a marked increase in relaxation time of isolated papillary muscle suggesting the involvement of additional cyclic AMP-independent mechanisms of action.