This approach is classical isosteric replacement of amide to azole. The potency of azole compounds approaches to the original Merck's amide compound, L-870,810.
Merck has a fascinating in vivo model!! Human P450 expressing mouse models may have the ability to generate major human metabolites and eliminate or reduce the formation of mouse specific metabolites. When compared to the current strategy for handling metabolite challenges (i.e., direct administration of metabolite), identifying an appropriate human P450 expressing model could provide a number of benefits. Such benefits include improved scientific relevance of the evaluation, decreased resource needs, and a possible reduction in the number of animals used. These benefits may ultimately improve the quality and speed by which promising new drug candidates are developed and delivered to patients.
Recently, GSK published GHS and Motilin (GPR38) for the treatment of gastric and upper intestinal stasis. For GHS, MK-0677 of Merck and Pfizer's compound advanced. On the other hand, GSK showed the first in class of small molecule clinical candidate as Motilin (GPR38) agonist. This paper focused avoiding TDI of CYP3A4. Replacement of the pyridyl ring with a two-carbon linker and replacement of the dimethylpiperazine with methylpiperazine improved TDI profile. I'm interested in mechanism of metabolic inactivation of pyridine ring.
This paper was disclosed data reviewed from 17 molecules in the Lilly portfolio for which there were in vitro data and a radiolabeled study in humans. Twelve example cases are presented in detail to demonstrate trends for when in vitro data adequately predicted in vivo (41%), when in vitro data underpredicted the circulating metabolites (35%), and when in vitro data overpredicted the circulating metabolites (24%). The in vitro data were also less predictive for N-glucuronidations and non-P450-mediated cleavage reactions. Although the in vitro data were better at predicting clearance pathways, the data set often failed to predict the quantity of metabolites, which is needed in consideration of whether or not a “disproportionate” metabolite may be circulating in human plasma. This article is very interesting because insight of Lilly's pipeline's DMPK correlation.
Molecular Hybridization!! This SBDD is a drug design of merging two different chemotypes. Efavirenz is the first-generation NNRTI, which is very susceptible to single-point resistance mutations within RT. On the other hand, capravirine is the second-generation NNRTI, which exhibits good potency to the mutant. Pfizer's medicinal chemists selected well-established efavirenz template, and modified by information of capravirine's crystal structure, so they discovered novel second-generation NNRTI. They designed indazole as scaffold with hydrogen bonding nitrogen as key interaction. Dichlorophenyl moiety of capravirine should be important to show a potency of the mutant, so they introduced this part at 4-position of indazole. But, they introduced dicyanophenyl instead of dichlorophenyl, because of amenable indazole synthetic chemistry and more druggable starting point (ex. reducing lipophilicity). 3-positon of indazole was superposed at CF3 of efavirenz and iPr of capravirine. 3-methyl indazole showed good potency but this compound had bioactivation risk. They explained 3-methyl indazole was an obvious similar with 3-methyl indole, which exhibits toxicity due to H-atom abstraction from the methyl group, followed by single electron oxidation to form the electrophilic imine-methide. To avoid this bioactivation risk, they modified 3-position, then they discovered ethyl group is enough substitution. Because Cl of efavirenz is superposed at 5-position of indazole, they introduced Cl at 5-position, but Cl did not enhance very much. It is interesting that smaller F increased potency. Chlorination and fluorination of eletron-deficient indazole are key step as synthetic chemistry.
Wyeth's medicinal chemists designed an orally available small molecule from the hexapeptide. There are many reports to design small molecule from 3 or 4 peptide as gamma-turn or beta-turn, but I guess drug design from larger hexapeptide should be more difficult. SAR of hexapeptide of GAP-junction modifier is followed; 1) the terminal tyrosine and glycine are essential, 2) cyclic peptide showed potency, 3) it is possible to change of glycine and alanine spacer, 4) proline and hydroxyproline are important. NOE observation of terminal tyrosine and glycine indicated the hexapeptide preferred to form horse-shoe structure. Based on this information, they made pharmacophore model, screened focused library, then obtained 340 compounds hits. Further they investigated solubility, PAMPA permeability, metabolic stability, plasma stability, CYP inhibition, clustering, efficacy, pharmacokinetics to obtain GAP-134 (now Phase-I).
Selective delta-opioid agonists have received interest in depression, cardioprotection and overactive bladder as well as pain. Pfizer's cell line functional assay discovered a singleton hit. Singleton rescue was examined by library synthesis. On the other hand, Pfizer's chemists designed a new template as aminopiperidine, which was applied from fentanyl originally reduced chiral center of morphine. The third temple was designed as spiropiperidine related to ORL-1 compounds. It is interesting that ClogP > 1 for the compound meant an 80% chance of hERG < 10 micro M.