The drug design was focused on improvement of metabolic stability and biaoavailablity. The first approach was to replace aryl moiety at the 1 position of pyrazoles moiety with smaller alkyl groups. This strategy was successful to maintain the potency, but did not improve metabolic stability very much. Next design was to modify the metabolically unstable 3, and 4 position of pyrazoles. Replacement of the pydirine with 3,5-diF-benzene improved metabolic stability. Finally, they revisited the 1 position of pyrazole, and then they introduced a cyanoethyl group to reduce lipophilicity to discover a selective orally available and good brain-penetrable ORL1 antagonist, MK-1925.
A new histamine H3 receptor (H3R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogues were made based on a previously identified conessine-based H3R antagonist series. While the first analogues 11 and 15 showed no antagonistic activity to H3R, the mere addition of a key moiety found in the reference compound 7 (ABT-239) elevated the series to high potency at H3R. The hybrid structure (16b) was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by 17a having a human H3 Ki of 0.54 nM, rat H3 Ki of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t1/2 of 2.4 h).
SF5 group looks like an unusual substituent in medicinal chemistry. In fact, this novel substituent had been largely ignored by the chemical community for several decades. But, SF5 has a fascinating property. SF5 is a perfectly stable building block under physiological conditions. The SF5 group bears much similarity to the CF3, but it is even more electronegative (Hammet substituent constants: SF6: +0.68; CF3: +0.54) and has a higher lipophilicity (Hansch hydrophobicity constants: SF6: 1.51; CF3: 1.09). So, SF5 has been characterized as a "super-trifluoromethyl" group in the literature. Its strong polarity in combination with high lipophilicity and thermal stability renders the SF5 group a highly interesting structural motif in medicinal chemistry.
The number of aromatic ring seems to be related with probability of drug development. As increasing the number of aromatic ring, lipophilicity tends to increase, solubility tends to decrease, CYP and hERG inhibition tends to be strong, and protein binding tends to be strong. The average number of aromatic rings in preclinical candidate is 3.3, in contrast to the average number of aromatic rings in those compounds that were still in the pipeline at POC, which is 2.3. The average number of aromatic rings in oral drugs is 1.6. The number of aromatic ring is regarded as the druggability.
TransTech Pharma has developed orally active GLP-1 agonists. TTP054 may be on Phase-II trial.
I guess this patent is the first disclosure of Transtech's GLP-1 agonists. Ex 15 shows 145 nM full agonist activity.
Unbelievable breaking news! This is class B GPCR agonist. It's very difficult to discover non-peptide ligands. It is more surprising that TTP054 was orally efficient and developed Phase-Ib/IIa.
(WO/2009/126709) LIGANDS FOR THE GLP-1 RECEPTOR AND METHODS FOR DISCOVERY THEREOF
Recently, TransTech Pharma disclosed that TTP-054, a non peptide orally available GLP-1 agonist, has been developed under Phase-IIa.
Usually, de novo generating homology model of GPCR, particularly class B, is not reliable. But TransTech's scientists achieved to discover a very difficult target ligand by de novo GPCR and virtuall screening (Fig. 4).